Quinazoline derivatives for treatment of tumours

ABSTRACT

The invention concerns quinazoline derivatives of Formula (I) wherein each of Q 1 , Z, m, R 1 , R 2 , R 3  and Q 2  have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an anti-invasive agent in the containment and/or treatment of solid tumour disease.

[0001] The invention concerns certain novel quinazoline derivatives, orpharmaceutically-acceptable salts thereof, which possess anti-tumouractivity and are accordingly useful in methods of treatment of the humanor animal body. The invention also concerns processes for themanufacture of said quinazoline derivatives, to pharmaceuticalcompositions containing them and to their use in therapeutic methods,for example in the manufacture of medicaments for use in the preventionor treatment of solid tumour disease in a warm-blooded animal such asman.

[0002] Many of the current treatment regimes for cell proliferationdiseases such as psoriasis and cancer utilise compounds which inhibitDNA synthesis. Such compounds are toxic to cells generally but theirtoxic effect on rapidly dividing cells such as tumour cells can bebeneficial. Alternative approaches to anti-tumour agents which act bymechanisms other than the inhibition of DNA synthesis have the potentialto display enhanced selectivity of action.

[0003] In recent years it has been discovered that a cell may becomecancerous by virtue of the transformation of a portion of its DNA intoan oncogene i.e. a gene which, on activation, leads to the formation ofmalignant tumour cells (Bradshaw, Mutagenesis, 1986, 1, 91). Severalsuch oncogenes give rise to the production of peptides which arereceptors for growth factors. Activation of the growth factor receptorcomplex subsequently leads to an increase in cell proliferation. It isknown, for example, that several oncogenes encode tyrosine kinaseenzymes and that certain growth factor receptors are also tyrosinekinase enzymes (Yarden et al., Ann. Rev. Biochem., 1988, 57, 443; Larsenet al., Ann. Reports in Med. Chem., 1989, Chpt. 13). The first group oftyrosine kinases to be identified arose from such viral oncogenes, forexample pp60^(v-Src) tyrosine kinase (otherwise known as v-Src), and thecorresponding tyrosine kinases in normal cells, for example pp60^(Src)tyrosine kinase (otherwise known as c-Src).

[0004] Receptor tyrosine kinases are important in the transmission ofbiochemical signals which initiate cell replication. They are largeenzymes which span the cell membrane and possess an extracellularbinding domain for growth factors such as epidermal growth factor 30(EGF) and an intracellular portion which functions as a kinase tophosphorylate tyrosine amino acids in proteins and hence to influencecell proliferation. Various classes of receptor tyrosine kinases areknown (Wilks, Advances in Cancer Research, 1993, 60, 43-73) based onfamilies of growth factors which bind to different receptor tyrosinekinases. The classification includes Class I receptor tyrosine kinasescomprising the EGF family of receptor tyrosine kinases such as the EGF,TGFα, Neu and erbB receptors, Class II receptor tyrosine kinasescomprising the insulin family of receptor tyrosine kinases such as theinsulin and IGFI receptors and insulin-related receptor (IRR) and ClassIII receptor tyrosine kinases comprising the platelet-derived growthfactor (PDGF) family of receptor tyrosine kinases such as the PDGFα,PDGFβ and colony-stimulating factor 1 (CSF1) receptors.

[0005] It is also known that certain tyrosine kinases belong to theclass of non-receptor tyrosine kinases which are located intracellularlyand are involved in the transmission of biochemical signals such asthose that influence tumour cell motility, dissemination andinvasiveness and subsequently metastatic tumour growth (Ullrich et al.,Cell, 1990, 61, 203-212, Bolen et al., FASEB J., 1992, 6, 3403-3409,Brickell et al., Critical Reviews in Oncogenesis, 1992, 3, 401-406,Bohlen et al., Oncogene, 1993, 8, 2025-2031, Courtneidge et al., Semin.Cancer Biol., 1994, 5, 239-246, Lauffenburger et al., Cell, 1996, 84,359-369, Hanks et al., BioEssays, 1996, 19, 137-145, Parsons et al.,Current Opinion in Cell Biology, 1997, 9 187-192, Brown et al.,Biochimica et Biophysica Acta, 1996, 1287, 121-149 and Schlaepfer etal., Progress in Biophysics and Molecular Biology, 1999, 71, 435-478).Various classes of non-receptor tyrosine kinases are known including theSrc family such as the Src, Lyn, Fyn and Yes tyrosine kinases, the Ab1family such as Ab1 and Arg and the Jak family such as Jak 1 and Tyk 2.

[0006] It is known that the Src family of non-receptor tyrosine kinasesare highly regulated in normal cells and in the absence of extracellularstimuli are maintained in an inactive conformation. However, some Srcfamily members, for example c-Src tyrosine kinase, is frequentlysignificantly activated (when compared to normal cell levels) in commonhuman cancers such as gastrointestinal cancer, for example colon, rectaland stomach cancer (Cartwright et al., Proc. Natl. Acad. Sci. USA, 1990,87, 558-562 and Mao et al., Oncogene, 1997, 15, 3083-3090), and breastcancer (Muthuswanmy et al., Oncogene, 1995, 11, 1801-1810). The Srcfamily of non-receptor tyrosine kinases has also been located in othercommon human cancers such as non-small cell lung cancers (NSCLCs)including adenocarcinomas and squamous cell cancer of the lung(Mazurenko et al., European Journal of Cancer, 1992, 28, 372-7), bladdercancer (Fanning et al., Cancer Research, 1992, 52, 1457-62), oesophagealcancer (Jankowski et al., Gut, 1992, 33, 1033-8), cancer of theprostate, ovarian cancer (Wiener et al., Clin. Cancer Research, 1999, 52164-70) and pancreatic cancer (Lutz et al., Biochem. and Biophys. Res.Comm., 1998, 243, 503-8). As further human tumour tissues are tested forthe Src family of non-receptor tyrosine kinases it is expected that itswidespread prevalance will be established.

[0007] It is further known that the predominant role of c-Srcnon-receptor tyrosine kinase is to regulate the assembly of focaladhesion complexes through interaction with a number of cytoplasmicproteins including, for example, focal adhesion kinase and paxillin. Inaddition c-Src is coupled to signalling pathways that regulate the actincytoskeleton which facilitates cell motility. Likewise, important rolesare played by the c-Src, c-Yes and c-Fyn non-receptor tyrosine kinasesin integrin mediated signalling and in disrupting cadherin-dependentcell-cell junctions (Owens et al., Molecular Biology of the Cell, 2000,11, 51-64 and Klinghoffer et al., EMBO Journal, 1999, 18, 2459-2471).Cellular motility is necessarily required for a localised tumour toprogress through the stages of dissemination into the blood stream,invasion of other tissues and initiation of metastatic tumour growth.For example, colon tumour progression from localised to disseminated,invasive metastatic disease has been correlated with c-Src non-receptortyrosine kinase activity (Brunton et al., Oncogene, 1997, 14) 283-293,Fincham et al., EMBO J, 1998, 17, 81-92 and Verbeek et al., Exp. CellResearch, 1999, 248, 531-537).

[0008] Accordingly it has been recognised that an inhibitor of suchnon-receptor tyrosine kinases should be of value as a selectiveinhibitor of the motility of tumour cells and as a selective inhibitorof the dissemination and invasiveness of mammalian cancer cells leadingto inhibition of metastatic tumour growth. In particular an inhibitor ofsuch non-receptor tyrosine kinases should be of value as ananti-invasive agent for use in the containment and/or treatment of solidtumour disease.

[0009] We have now found that surprisingly certain quinazolinederivatives possess potent anti-tumour activity. Without wishing toimply that the compounds disclosed in the present invention possesspharmacological activity only by virtue of an effect on a singlebiological process, it is believed that the compounds provide ananti-tumour effect by way of inhibition of one or more of thenon-receptor tyrosine-specific protein kinases that are involved in thesignal transduction steps which lead to the invasiveness and migratoryability of metastasising tumour cells. In particular, it is believedthat the compounds of the present invention provide an anti-tumoureffect by way of inhibition of the Src family of non-receptor tyrosinekinases, for example by inhibition of one or more of c-Src, c-Yes andc-Fyn.

[0010] It is also known that c-Src non-receptor tyrosine kinase enzymeis involved in the control of osteoclast-driven bone resorption (Sorianoet al., Cell, 1991, 64, 693-702; Boyce et al., J. Clin. Invest., 1992,90, 1622-1627; Yoneda et al., J. Clin. Invest. 1993, 91, 2791-2795 andMissbach et al., Bone, 1999, 24, 437-49). An inhibitor of c-Srcnon-receptor tyrosine kinase is therefore of value in the prevention andtreatment of bone diseases such as osteoporosis, Paget's disease,metastatic disease in bone and tumour-induced hypercalcaemia.

[0011] The compounds of the present invention are also useful ininhibiting the uncontrolled cellular proliferation which arises fromvarious non-malignant diseases such as inflammatory diseases (forexample rheumatoid arthritis and inflammatory bowel disease), fibroticdiseases (for example hepatic cirrhosis and lung fibrosis),glomerulonephritis, multiple sclerosis, psoriasis, hypersensitivityreactions of the skin, blood vessel diseases (for exampleatherosclerosis and restenosis), allergic asthma, insulin-dependentdiabetes, diabetic retinopathy and diabetic nephropathy.

[0012] Generally the compounds of the present invention possess potentinhibitory activity against the Src family of non-receptor tyrosinekinases, for example by inhibition of c-Src and/or c-Yes, whilstpossessing less potent inhibitory ativity against other tyrosine kinaseenzymes such as the receptor tyrosine kinases, for example EGF receptortyrosine kinase and/or VEGF receptor tyrosine kinase. Furthermore,certain compounds of the present invention, possess substantially betterpotency against the Src family of non-receptor tyrosine kinases, forexample c-Src and/or c-Yes, than against EGF receptor tyrosine kinase orVEGF receptor tyrosine kinase. Such compounds possess sufficient potencyagainst the Src family of non-receptor tyrosine kinases, for examplec-Src and/or c-Yes, that they may be used in an amount sufficient toinhibit, for example, c-Src and/or c-Yes whilst demonstrating littleactivity against EGF receptor tyrosine kinase or VEGF receptor tyrosinekinase.

[0013] According to one aspect of the invention there is provided aquinazoline derivative of the Formula I

[0014] wherein m is 0, 1, 2 or 3;

[0015] each R¹ group, which may be the same or different, is selectedfrom halogeno, trifluoromethyl, cyano, isocyano, nitro, hydroxy,mercapto, amino, formyl, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl,(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,(2-6C)alkanoyloxy, (2-6C)alkanoylamino,N-(1-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino,N-(1-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino,N-(1-6C)alkyl-(3-6C)alkynoylamino, N-(1-6C)alkylsulphamoyl,N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino andN-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of theformula:

Q³-X¹—

[0016] wherein X¹ is a direct bond or is selected from O, S, SO, SO²,N(R⁴), CO, CH(OR⁴), CON(R⁴), N(R⁴)CO, SO₂N(R⁴), N(R⁴)SO₂, OC(R⁴)₂,SC(R⁴)₂ and N(R⁴)C(R⁴)₂, wherein R⁴ is hydrogen or (1-6C)alkyl, and Q³is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl, or (R¹)_(m) is(1-3C)alkylenedioxy,

[0017] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin a R¹ substituent are optionally separated by the insertion intothe chain of a group selected from O, S, SO, SO₂, N(R⁵), CO, CH(OR⁵),CON(R⁵), N(R⁵)CO, SO₂N(R⁵), N(R⁵)SO₂, CH═CH and C≡C wherein R⁵ ishydrogen or (1-6C)alkyl,

[0018] and wherein any CH₂═CH— or HC≡C— group within a R¹ substituentoptionally bears at the terminal CH₂═ or HC≡ position a substituentselected from halogeno, carboxy, carbamoyl, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl anddi-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula:

Q⁴-X²—

[0019] wherein X² is a direct bond or is selected from CO and N(R⁶)CO,wherein R⁶ is hydrogen or (1-6C)alkyl, and Q⁴ is aryl, aryl-(1-6C)alkyl,heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl,

[0020] and wherein any CH₂ or CH₃ group within a R¹ substituentoptionally bears on each said CH₂ or CH₃ group one or more halogeno or(1-6C)alkyl substituents or a substituent selected from hydroxy, cyano,amino, carboxy, carbamoyl, (1-6C)alkoxy, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,(1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,or from a group of the formula:

—X³-Q⁵

[0021] wherein X³ is a direct bond or is selected from O, S, SO, OSO₂,N(R⁷), CO, CH(OR⁷), CON(R⁷), N(R⁷)CO, SO₂N(R⁷), N(R⁷)SO₂, C(R⁷)₂O,C(R⁷)₂S and N(R⁷)C(R⁷)₂, wherein R⁷ is hydrogen or (1-6C)alkyl, and Q₅is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl,

[0022] and wherein any aryl, heteroaryl or heterocyclyl group within asubstituent on R¹ optionally bears 1, 2 or 3 substituents, which may bethe same or different, selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl,(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,(2-6C)alkanoyloxy, (2-6C)alkanoylamino,N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl,N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino andN-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of theformula:

—X—R⁸

[0023] wherein X⁴ is a direct bond or is selected from 0 and N(R⁹),wherein R⁹ is hydrogen or (1-6C)alkyl, and R⁸ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl or(1-6C)alkoxycarbonylamino-(1-6C)alkyl, or from a group of the formula:

—X⁵-Q⁶

[0024] wherein X⁵ is a direct bond or is selected from O, CO and N(R¹⁰),wherein R¹⁰ is hydrogen or (1-6C)alkyl, and Q⁶ is aryl,aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from halogeno, (1-6C)alkyland (1-6C)alkoxy,

[0025] and wherein any heterocyclyl group within a substituent on R¹optionally bears 1 or 2 oxo or thioxo substituents;

[0026] R² is hydrogen or (1-6C)alkyl;

[0027] R³ is hydrogen or (1-6C)alkyl;

[0028] Z is a direct bond or is selected from O, S, SO, SO₂, N(R¹¹), CO,CH(OR¹¹), CON(R¹¹), N(R¹¹)CO, SO₂N(R¹¹), N(R¹¹)SO₂, OC(R¹¹)₂, SC(R¹¹)₂and N(R¹¹)C(R¹¹)₂, wherein R¹¹ is hydrogen or (1-6C)alkyl;

[0029] Q¹ is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl, or, when Z is a direct bond orO, Q¹ may be (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl,halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl,cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, (1-6C)alkylthio-(1-6C)alkyl,(1-6C)alkylsulphinyl-(1-6C)alkyl or (1-6C)alkylsulphonyl-(1-6C)alkyl,

[0030] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin the Q¹-Z— group are optionally separated by the insertion intothe chain of a group selected from O, S, SO, SO₂, N(R¹²), CO, CH(OR¹²),CON(R¹²), N(R¹²)CO, SO₂N(R¹²), N(R₁₂)SO₂, CH═CH and C≡C wherein R¹² ishydrogen or (1-6C)alkyl,

[0031] and wherein any CH₂═CH— or HC≡C— group within the Q¹-Z— groupoptionally bears at the terminal CH₂═ or HC≡ position a substituentselected from halogeno, carboxy, carbamoyl, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl anddi-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula:

Q⁷-X⁶—

[0032] wherein X⁶ is a direct bond or is selected from CO and N(R¹³)CO,wherein R¹³ is hydrogen or (1-6C)alkyl, and Q⁷ is aryl,aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl,

[0033] and wherein any CH₂ or CH₃ group within the Q¹-Z— groupoptionally bears on each said CH₂ or CH₃ group one or more halogeno or(1-6C)alkyl substituents or a substituent selected from hydroxy, cyano,amino, carboxy, carbamoyl, (1-6C)alkoxy, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,(1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,or from a group of the formula:

—X⁷-Q⁸

[0034] wherein X⁷ is a direct bond or is selected from O, S, SO, SO₂,N(R¹⁴), CO, CH(OR¹⁴), CON(R¹⁴), N(R¹⁴)CO, SO₂N(R¹⁴), N(R¹⁴)SO₂,C(R¹⁴)₂O, C(R¹⁴)₂S and N(R¹⁴)C(R¹⁴)₂, wherein R¹⁴ is hydrogen or(1-6C)alkyl, and Q⁸ is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl,

[0035] and wherein any aryl, heteroaryl or heterocyclyl group within theQ¹-Z— group optionally bears 1, 2 or 3 substituents, which may be thesame or different, selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl,(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,(2-6C)alkanoyloxy, (2-6C)alkanoylamino,N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl,N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino andN-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of theformula:

—X⁸—R¹⁵

[0036] wherein X⁷ is a direct bond or is selected from O and N(R¹⁶),wherein R¹⁶ is hydrogen or (1-6C)alkyl, and R¹⁵ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl ordi-[(1-6C)alkyl]amino-(1-6C)alkyl, or from a group of the formula:

—X⁹-Q⁹

[0037] wherein X⁹ is a direct bond or is selected from O, CO and N(R¹⁷),wherein R¹⁷ is hydrogen or (1-6C)alkyl, and Q⁹ is aryl,aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from halogeno, (1-6C)alkyland (1-6C)alkoxy,

[0038] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo or thioxo substituents; and

[0039] Q² is an aryl group of formula Ia

[0040] wherein G¹ is selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl,(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,(2-6C)alkanoyloxy, (2-6C)alkanoylamino,N-(1-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino,N-(1-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino,N-(1-6C)alkyl-(3-6C)alkynoylamino, N-(1-6C)alkylsulphamoyl,N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino andN-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of theformula:

—X¹⁰—R¹⁸

[0041] wherein X¹⁰ is a direct bond or is selected from O and N(R¹⁹),wherein R¹⁹ is hydrogen or (1-6C)alkyl, and R¹⁸ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl ordi-[(l-6C)alkyl]amino-(1-6C)alkyl, or from a group of the formula:

—X¹¹-Q¹⁰

[0042] wherein X¹¹ is a direct bond or is selected from O, S, SO, SO₂,N(R²⁰), CO, CH(OR²⁰), CON(R²⁰), N(²⁰)CO, SO₂N(R²⁰), N(R²⁰)SO₂, C(R²⁰)₂O,C(R²⁰)₂S and N(R²⁰)C(R²⁰)₂, wherein R²⁰ is hydrogen or (1-6C)alkyl, andQ¹⁰ is aryl, aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl which optionally bears 1 or 2substituents, which may be the same or different, selected fromhalogeno, (1-6C)alkyl and (1-6C)alkoxy, and any heterocyclyl groupwithin Q¹⁰ optionally bears 1 or 2 oxo or thioxo substituents,

[0043] and each of G², G³, G⁴ and G⁵, which may be the same ordifferent, is selected from hydrogen, halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl,(1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino,

[0044] or G¹ and G² together form a group of formula: —CH═CH—CH═CH—,—N═CH—CH═CH—, —CH═N—CH═CH—, —CH═CH—N═CH—, —CH═CH—CH═N—, —N═CH—N═CH—,—CH═N—CH═N—, —N═CH—CH═N—, —N═N—CH═CH—, —CH═CH—N═N—, —CH═CH—O—,—O—CH═CH—, —CH═CH—S—, —S—CH═CH—, —CH₂—CH₂—O—, —O—CH₂—CH₂—, —CH₂—CH₂—S—,—S—CH₂—CH₂—, —O—CH₂—O—, —O—CH₂—CH₂—O—, —S—CH₂—S—, —S—CH₂—CH₂—S—,—CH═CH—NH—, —NH—CH═CH—, —CH₂—CH₂—NH—, —NH—CH₂—CH₂—, —N═CH—NH—,—NH—CH═N—, —NH—CH₂—NH—, —O—CH—═N—, —N═CH—O—, —S—CH═N—, —N═CH—S—,—O—CH₂—NH—, —NH—CH₂—O—, —S—CH₂—NH—, —NH—CH₂—S—, —O—N═CH—, —CH═N—O—,—S—N═CH—, —CH═N—S—, —O—NH—CH₂—, —CH₂—NH—O—, —S—NH—CH₂—, —CH₂—NH—S—,—NH—N═CH—, —CH═N—NH—, —NH—NH—CH₂—, —CH₂—NH—NH—, —N═N—NH— or —NH—N═N—,

[0045] or G¹ has any of the meanings defined hereinbefore and G² and G³together or G³ and G⁴ together form a group of formula: —CH═CH—CH═CH—,—N═CH—CH═CH—, —CH═N—CH═CH—, —CH═CH—N═CH—, —CH═CH—CH═N—, —N═CH—N═CH—,—CH═N—CH═N—, —N═CH—CH═N—, —N═N—CH═CH—, —CH═CH—N═N—, —CH═CH—O—,—O—CH═CH—, —CH═CH—S—, —S—CH═CH—, —CH₂—CH₂—O—, —O—CH₂—CH₂—, —CH₂—CH₂—S—,—S—CH₂—CH₂—, —O—CH₂—O—, —O—CH₂—CH ,—O—, —S—CH₂—S—, —S—CH₂—CH₂—S—,—CH═CH—NH—, —NH—CH═CH—, —CH₂—CH₂—NH—, —NH—CH₂—CH₂—, —N═CH—NH—,—NH—CH═N—, —NH—CH₂—NH—, —O—CH═N—, —N═CH—O—, —S—CH═N—, —N═CH—S—,—O—CH₂—NH—, —NH—CH₂—O—, —S—CH2—NH—, —NH—CH₂—S—, —O—N═CH—, —CH═N—O—,—S—N═CH—, —CH═N—S—, —O—NH—CH₂—, —CH₂—NH—O—, —S—NH—CH₂—, —CH₂—NH—S—,—NH—N═CH—, —CH═N—NH—, —NH—NH—CH₂—, —CH,—NH—NH—, —N═N—NH— or —NH—N═N—,

[0046] and the 9- or 10-membered bicyclic heteroaryl or heterocyclicring formed when G¹ and G² together, G² and G³ together or G³ and G⁴together are linked optionally bears on the heteroaryl or heterocyclicportion of the bicyclic ring 1, 2 or 3 substituents, which may be thesame or different, selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl,(1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, and anybicyclic heterocyclic ring so formed optionally bears 1 or 2 oxo orthioxo groups;

[0047] or a pharmaceutically-acceptable salt thereof.

[0048] According to a further aspect of the invention there is provideda quinazoline derivative of the Formula I wherein each of m, R¹, R², R³and Q² has any of the meanings defined hereinbefore and

[0049] Z is a direct bond or is selected from O, S, SO, SO₂, N(R¹¹), CO,CH(OR¹¹), CON(R¹¹), N(R¹¹)CO, SO₂N(R¹¹), N(R¹¹)SO₂, OC(R¹¹)₂, SC(R¹¹)₂and N(R¹¹)C(R¹)₂, wherein R¹¹ is hydrogen or (1-6C)alkyl; and

[0050] Q₁ is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl,

[0051] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin the Q¹-Z— group are optionally separated by the insertion intothe chain of a group selected from O, S, SO, SO₂N(R¹²), CO, CH(OR¹²),CON(R¹²) N(R¹²)CO, SO₂N(R¹²), N(R¹²)SO₂, CH═CH and C≡C wherein R¹² ishydrogen or (1-6C)alkyl,

[0052] and wherein any CH₂ or CH₃ group within the Q¹-Z— groupoptionally bears on each said CH₂ or CH₃ group one or more halogeno or(1-6C)alkyl substituents or a substituent selected from hydroxy, cyano,amino, carboxy, carbamoyl, (1-6C)alkoxy, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl(1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,or from a group of the formula:

—X⁷-Q⁸

[0053] wherein X⁷ is a direct bond or is selected from O, S, SO, SO₂,N(R¹⁴), CO, CH(OR¹⁴), CON(R¹⁴), N(R¹⁴)CO, SO₂N(R¹⁴), N(R¹⁴)SO₂,C(R¹⁴)₂O, C(R¹⁴)₂S and N(R¹⁴)C(R¹⁴)₂, wherein R¹⁴ is hydrogen or(1-6C)alkyl, and Q⁸ is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl,

[0054] and wherein any aryl, heteroaryl or heterocyclyl group within theQ¹-Z— group optionally bears 1, 2 or 3 substituents, which may be thesame or different, selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl,(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,(1-6C)alkylamino, di-[(1-6C)alkyl] amino, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbomyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,(1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,or from a group of the formula:

—X⁸—R¹⁵

[0055] wherein X⁸ is a direct bond or is selected from O and N(R¹⁶),wherein R¹⁶ is hydrogen or (1-6C)alkyl, and R¹⁵ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl ordi-[(1-6C)alkyl]amino-(1-6C)alkyl, or from a group of the formula:

—X⁹-Q⁹

[0056] wherein X⁹ is a direct bond or is selected from O, CO and N(R¹⁷),wherein R¹⁷ is hydrogen or (1-6C)alkyl, and Q⁹ is aryl,aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from-halogeno, (1-6C)alkyland (1-6C)alkoxy,

[0057] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo or thioxo substituents.

[0058] According to a further aspect of the invention there is provideda quinazoline derivative of the Formula I wherein each of m, R¹, R², R³and Q² has any of the meanings defined hereinbefore and

[0059] Z is selected from O, S, SO, SO₂, N(R¹¹), CO, CH(OR¹¹), CON(R¹¹),N(R¹¹)CO, SO₂N(R¹¹), N(R¹¹)SO₂, OC(R¹¹)₂, SC(R¹¹)₂ and N(R¹¹)C(R¹¹)₂,wherein R¹¹ is hydrogen or (1-6C)alkyl; and

[0060] Q¹ is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl,(3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl,

[0061] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin the Q¹-Z— group are optionally separated by the insertion intothe chain of a group selected from O, S, SO, SO₂, N(R¹²), CO, CH(OR¹²),CON(R¹²), N(R¹²)CO, SO₂N(R¹²), N(R¹²)SO₂, CH═CH and C≡C wherein R¹² ishydrogen or (1-6C)alkyl,

[0062] and wherein any CH₂ or CH₃ group within the Q¹-Z— groupoptionally bears on each said CH₂ or CH₃ group one or more halogeno or(1-6C)alkyl substituents or a substituent selected from hydroxy, cyano,amino, carboxy, carbamoyl, (1-6C)alkoxy, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,(1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,or from a group of the formula:

—X⁷-Q⁸

[0063] wherein X⁷ is a direct bond or is selected from O, S, SO, SO₂,N(R¹⁴), CO, CH(OR¹⁴), CON(R¹⁴), N(R¹⁴)CO, SO₂N(R¹⁴), N(R¹⁴)SO₂,C(R¹⁴)₂O, C(R¹⁴)₂S and N(R¹⁴)C(R¹⁴)₂, wherein R¹⁴ is hydrogen or(1-6C)alkyl, and Q⁸ is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl,

[0064] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1, 2 or 3 substituents, which may be the same ordifferent, selected from halogeno, trifluoromethyl, cyano, nitro,hydroxy, amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl,(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,(2-6C)alkanoyloxy, (2-6C)alkanoylamino,N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl,N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino andN-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of theformula:

—X⁸—R¹⁵

[0065] wherein X⁸ is a direct bond or is selected from O and N(R¹⁶),wherein R¹⁶ is hydrogen or (1-6C)alkyl, and R¹⁵ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl ordi-[(1-6C)alkyl]amino-(1-6C)alkyl, or from a group of the formula:

—X⁹-Q⁹

[0066] wherein X⁹ is a direct bond or is selected from O, CO and N(R¹⁷),wherein R¹⁷ is hydrogen or (1-6C)alkyl, and Q⁹ is aryl,aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from halogeno, (1-6C)alkyland (1-6C)alkoxy,

[0067] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo or thioxo substituents.

[0068] According to a further aspect of the invention there is provideda quinazoline derivative of the Formula I

[0069] wherein m is 0, 1, 2 or 3;

[0070] each R¹ group, which may be the same or different, is selectedfrom halogeno, trifluoromethyl, cyano, isocyano, nitro, hydroxy,mercapto, amino, formyl, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl,(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,(2-6C)-4alkanoyloxy, (2-6C)alkanoylamino,N-(1-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino,N-(1-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino,N-(1-6C)alkyl-(3-6C)alkynoylamino, N-(1-6C)alkylsulphamoyl,N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino andN-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of theformula:

Q³-X¹—

[0071] wherein X¹ is a direct bond or is selected from O, S, SO, SO₂,N(R⁴), CO, CH(OR⁴), CON(R⁴), N(R⁴)CO, SO₂N(R⁴), N(R⁴)SO₂, OC(R⁴)₂,SC(R⁴)₂ and N(R⁴)C(R⁴)₂, wherein R⁴ is hydrogen or (1-6C)alkyl, and Q³is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl, or (R¹)_(m) is(1-3C)alkylenedioxy,

[0072] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin a R¹ substituent are optionally separated by the insertion intothe chain of a group selected from O, S, SO, SO₂, N(R⁵), CO, CH(OR⁵),CON(R⁵), N(R)CO, SO₂N(R⁵), N(R⁵)SO₂, CH═CH and C≡C wherein R⁵ ishydrogen or (1-6C)alkyl,

[0073] and wherein any CH₂═CH— or HC≡C— group within a R¹ substituentoptionally bears at the terminal CH₂═ or HC≡ position a substituentselected from halogeno, carboxy, carbamoyl, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl anddi-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula:

Q⁴-X²—

[0074] wherein X² is a direct bond or is selected from CO and N(R⁶)CO,wherein R⁶is hydrogen or (1-6C)alkyl, and Q⁴ is aryl, aryl-(1-6C)alkyl,heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl,

[0075] and wherein any CH₂ or CH₃ group within a R¹ substituentoptionally bears on each said CH₂ or CH₃ group one or more halogeno or(1-6C)alkyl substituents or a substituent selected from hydroxy, cyano,amino, carboxy, carbamoyl, (1-6C)alkoxy, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,(1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,or from a group of the formula:

—X³-Q⁵

[0076] wherein X³ is a direct bond or is selected from O, S, SO, SO₂,N(R⁷), CO, CH(OR⁷), CON(R⁷), N(R⁷)CO, SO₂N(R⁷), N(R⁷)SO₂, C(R⁷)₂O,C(R⁷)₂S and N(R⁷)C(R⁷)₂, wherein R⁷ is hydrogen or (1-6C)alkyl, and Q⁵is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl,

[0077] and wherein any aryl, heteroaryl or heterocyclyl group within asubstituent on R¹ optionally bears 1, 2 or 3 substituents, which may bethe same or different, selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl,(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,(2-6C)alkanoyloxy, (2-6C)alkanoylamino,N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl,N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino andN-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of theformula:

—X⁴—R⁸

[0078] wherein X⁴ is a direct bond or is selected from O and N(R⁹),wherein R⁹ is hydrogen or (1-6C)alkyl, and R⁸ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl or(1-6C)alkoxycarbonylamino-(1-6C)alkyl, or from a group of the formula:

—X⁵-Q⁶

[0079] wherein X⁵ is a direct bond or is selected from O and N(R¹⁰),wherein R¹⁰ is hydrogen or (1-6C)alkyl, and Q⁶ is aryl,aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from halogeno, (1-6C)alkyland (1-6C)alkoxy,

[0080] and wherein any heterocyclyl group within a substituent on R¹optionally bears 1 or 2 oxo or thioxo substituents;

[0081] R² is hydrogen or (1-6C)alkyl;

[0082] R³ is hydrogen or (1-6C)alkyl;

[0083] Z is a direct bond or is selected from O, S, SO, SO₂, N(R¹¹), CO,CH(OR¹¹), CON(R¹¹), N(R¹¹)CO, SO₂N(R¹¹), N(R¹¹)SO₂, OC(R¹¹)₂, SC(R¹¹)₂and N(R¹¹)C(R¹¹)₂, wherein R¹¹ is hydrogen or (1-6C)alkyl;

[0084] Q¹ is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl, or, when Z is a direct bond orO, Q¹ may be (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl,halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl,cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, (1-6C)alkylthio-(1-6C)alkyl,(1-6C)alkylsulphinyl-(1-6C)alkyl or (1-6C)alkylsulphonyl-(1-6C)alkyl,

[0085] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin the Q¹-Z— group are optionally separated by the insertion intothe chain of a group selected from O, S, SO, SO₂, N(R¹²), CO, CH(OR¹²),CON(R¹²), N(R¹²)CO, SO₂N(R¹²) N(R¹²)SO₂, CH═CH and C≡C wherein R¹² ishydrogen or (1-6C)alkyl,

[0086] and wherein any CH₂═CH— or HC≡C— group within the Q¹-Z— groupoptionally bears at the terminal CH₂═ or HC≡ position a substituentselected from halogeno, carboxy, carbamoyl, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl anddi-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula:

Q⁷-X⁶—

[0087] wherein X⁶ is a direct bond or is selected from CO and N(R¹³)CO,wherein R¹³ is hydrogen or (1-6C)alkyl, and Q⁷ is aryl,aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl,

[0088] and wherein any CH₂ or CH₃ group within the Q¹-Z— groupoptionally bears on each said CH₂ or CH₃ group one or more halogeno or(1-6C)alkyl substituents or a substituent selected from hydroxy, cyano,amino, carboxy, carbamoyl, (1-6C)alkoxy, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,(1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,or from a group of the formula:

—X⁷-Q⁸

[0089] wherein X⁷ is a direct bond or is selected from O, S, SO, SO₂,N(R¹⁴), CO, CH(OR¹⁴), CON(R¹⁴), N(R¹⁴)CO, SO₂N(R¹⁴), N(R¹⁴)SO₂,C(R¹⁴)₂O, C(R¹⁴)₂S and N(R¹⁴)C(R¹⁴)₂, wherein R¹⁴ is hydrogen or(1-6C)alkyl, and Q⁸ is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl,

[0090] and wherein any aryl, heteroaryl or heterocyclyl group within theQ¹-Z— group optionally bears 1, 2 or 3 substituents, which may be thesame or different, selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl,(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,(2-6C)alkanoyloxy, (2-6C)alkanoylamino,N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl,N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino andN-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of theformula:

—X⁸—R¹⁵

[0091] wherein X⁸ is a direct bond or is selected from O and N(R¹⁶),wherein R¹⁶ is hydrogen or (1-6C)alkyl, and R¹⁵ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl ordi-[(1-6C)alkyl]amino-(1-6C)alkyl, or from a group of the formula:

—X⁹-Q⁹

[0092] wherein X⁹ is a direct bond or is selected from O and N(R¹⁷),wherein R¹⁷ is hydrogen or (1-6C)alkyl, and Q⁹ is aryl,aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from halogeno, (1-6C)alkyland (1-6C)alkoxy,

[0093] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo or thioxo substituents; and

[0094] Q² is an aryl group of formula Ia

[0095] wherein G¹ is selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl,(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,(2-6C)alkanoyloxy, (2-6C)alkanoylamino,N-(1-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino,N-(1-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino,N-(1-6C)alkyl-(3-6C)alkynoylamino, N-(1-6C)alkylsulphamoyl,N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino andN-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of theformula:

—X¹⁰—R¹⁸

[0096] wherein X¹⁰ is a direct bond or is selected from O and N(R¹⁹),wherein R¹⁹ is hydrogen or (1-6C)alkyl, and R¹⁸ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl ordi-[(1-6C)alkyl]amino-(1-6C)alkyl, or from a group of the formula:

—X¹¹-Q¹⁰

[0097] wherein X¹¹ is a direct bond or is selected from O, S, SO, SO₂,N(R²⁰), CO, CH(OR²⁰), CON²⁰), N(R²⁰)CO, SO₂N(R²⁰), N(R²⁰)SO₂, C(R²⁰)₂O,C(R²⁰)₂S and N(R²)C(R²⁰)₂, wherein R²⁰ is hydrogen or (1-6C)alkyl, andQ¹⁰ is aryl, aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl which optionally bears 1 or 2substituents, which may be the same or different, selected fromhalogeno, (1-6C)alkyl and (1-6C)alkoxy, and any heterocyclyl groupwithin Q¹⁰ optionally bears 1 or 2 oxo or thioxo substituents,

[0098] and each of G², G³, G⁴ and G⁵, which may be the same ordifferent, is selected from hydrogen, halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl,(1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino,

[0099] or G¹ and G² together form a group of formula: —CH═CH—CH═CH—,—N═CH—CH═CH—, —CH═N—CH═CH—, —CH═CH—N═CH—, —CH═CH—CH═N—, —N═CH—N═CH—,—CH═N—CH═N—, —N═CH—CH═N—, —N═N—CH═CH—, —CH═CH—N═N—, —CH═CH—O—,—O—CH═CH—, —CH═CH—S—, —S—CH═CH—, —CH₂—CH₂—O—, —O—CH₂—CH₂—, —CH₂—CH₂—S—,—S—CH₂—CH₂—, —O—CH₂—O—, —O—CH₂—CH₂—O—, —S—CH₂—S—, —S—CH₂—CH₂—S—,—CH═CH—NH—, —NH—CH═CH—, —CH₂—CH₂—NH—, —NH—CH₂—CH₂—, —N═CH—NH—,—NH—CH═N—, —NH—CH₂—NH—, —O—CH═N—, —N═CH—O—, —S—CH═N—, —N═CH—S—,—O—CH₂—NH—, —NH—CH₂—O—, —S—CH₂—NH—, —NH—CH₂—S—, —O—N═CH—, —CH═N—O—,—S—N═CH—, —CH═N—S—, —O—NH—CH₂—, —CH₂—NH—O—, —S—NH—CH₂—, —CH₂—NH—S—,—NH—N═CH—, —CH═N—NH—, —NH—NH—CH₂—, —CH₂—NH—NH—, —N═N—NH— or —NH—N═N—,

[0100] or G¹ has any of the meanings defined hereinbefore and G² and G³together or G³ and G⁴ together form a group of formula: —CH═CH—CH═CH—,—N═CH—CH═CH—, —CH═N—CH═CH—, —CH═CH—N═CH—, —CH═CH—CH═N—, —N═CH—N═CH—,—CH═N—CH═N—, —N═CH—CH═N—, —N═N—CH═CH—, —CH═CH—N═N—, —CH═CH—O—,—O—CH═CH—, —CH═CH—S—, —S—CH═CH—, —CH₂—CH₂—O—, —O—CH₂—CH₂—, —CH₂—CH₂—S—,—S—CH₂—CH₂—, —O—CH₂—O—, —O—CH₂—CH₂—O—, —S—CH₂—S—, —S—CH₂—CH₂—S—,—CH═CH—NH—, —NH—CH═CH—, —CH₂—CH₂—NH—, —NH—CH₂—CH₂—, —N═CH—NH—,—NH—CH═N—, —NH—CH₂—NH—, —O—CH═N—, —N═CH—O—, —S—CH═N—, —N═CH—S—,—O—CH₂—NH—, —NH—CH₂—O—, —S—CH₂—NH—, —NH—CH₂—S—, —O—N═CH—, —CH—N—O—,—S—N═CH—, —CH═N—S—, —O—NH—CH₂—, —CH₂—NH—O—, —S—NH—CH₁₂—, —CH₂—NH—S—,—NH—N═CH—, —CH═N—NH—, —NH—NH—CH₂—, —CH₂—NH—NH—, —N═N—NH— or —NH—N═N—,

[0101] and the 9- or 10-membered bicyclic heteroaryl or heterocyclicring formed when G¹ and G² together, G² and G³ together or G³ and G⁴together are linked optionally bears on the heteroaryl or heterocyclicportion of the bicyclic ring 1, 2 or 3 substituents, which may be thesame or different, selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl,(1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, and anybicyclic heterocyclic ring so formed optionally bears 1 or 2 oxo orthioxo groups;

[0102] or a pharmaceutically-acceptable salt thereof.

[0103] According to a further aspect of the invention there is provideda quinazoline derivative of the Formula I wherein each of m, R¹, R², R³and Q² has any of the meanings defined hereinbefore and

[0104] Z is a direct bond or is selected from O, S, SO, SO₂, N(R¹¹), CO,CH(OR¹¹), CON(R¹¹), N(R¹¹)CO, SO₂N(R¹¹), N(R¹¹)SO₂, OC(R¹¹)₂, SC(R¹¹)₂and N(R¹¹)C(R¹¹)₂, wherein R¹¹ is hydrogen or (1-6C)alkyl; and

[0105] Q¹ is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl,

[0106] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin the Q¹-Z— group are optionally separated by the insertion intothe chain of a group selected from O, S, SO, SO₂, N(R¹²), CO, CH(O¹²),CON(R¹²), N(R¹²)CO, SO₂N(R¹²), N(R¹²)SO₂, CH═CH and C≡C wherein R¹² ishydrogen or (1-6C)alkyl,

[0107] and wherein any CH₂ or CH₃ group within the Q¹-Z— groupoptionally bears on each said CH₂ or CH₃ group one or more halogeno or(1-6C)alkyl substituents or a substituent selected from hydroxy, cyano,amino, carboxy, carbamoyl, (1-6C)alkoxy, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,(1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,or from a group of the formula:

X⁷-Q⁸

[0108] wherein X⁷ is a direct bond or is selected from O, S, SO, SO₂,N(R¹⁴), CO, CH(OR¹⁴), CON(R¹⁴), N(R¹⁴)CO, SO₂N(R¹⁴), N(R¹⁴)SO₂,C(R¹⁴)₂O, C(R¹⁴)₂S and N(R¹⁴)C(R¹⁴)₂, wherein R¹⁴ is hydrogen or(1-6C)alkyl, and Q⁸ is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl,

[0109] and wherein any aryl, heteroaryl or heterocyclyl group within theQ¹-Z— group optionally bears 1, 2 or 3 substituents, which may be thesame or different, selected from halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl,(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,(2-6C)alkanoyloxy, (2-6C)alkanoylamino,N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl,N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino andN-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of theformula:

—X⁸—R¹⁵

[0110] wherein X⁸ is a direct bond or is selected from O and N(R¹⁶),wherein R¹⁶ is hydrogen or (1-6C)alkyl, and R¹⁵ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl ordi-[(1-6C)alkyl]amino-(1-6C)alkyl, or from a group of the formula:

—X⁹-Q⁹

[0111] wherein X⁹ is a direct bond or is selected from O and N(R¹⁷),wherein R¹⁷ is hydrogen or (1-6C)alkyl, and Q⁹ is aryl,aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from halogeno, (1-6C)alkyland (1-6C)alkoxy,

[0112] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo or thioxo substituents.

[0113] According to a further aspect of the invention there is provideda quinazoline derivative of the Formula I wherein each of m, R¹, R², R³and Q² has any of the meanings defined hereinbefore and

[0114] Z is selected from O, S, SO, SO₂, N(R¹¹), CO, CH(OR¹¹), CON(R¹¹),N(R¹¹)CO, SO₂N(R¹¹), N(R¹¹)SO₂, OC(R¹¹)₂, SC(R¹¹)₂ and N(R¹¹)C(R¹¹)₂,wherein R¹¹ is hydrogen or (1-6C)alkyl; and

[0115] Q¹ is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl,(3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl,

[0116] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin the Q¹-Z— group are optionally separated by the insertion intothe chain of a group selected from O, S, SO, SO₂, N(R¹²), CO, CH(OR¹²),CON(R¹²), N(R¹²)CO, SO₂N(R¹²), N(R¹²)SO₂, CH═CH and C≡C wherein R¹² ishydrogen or (1-6C)alkyl,

[0117] and wherein any CH₂ or CH₃ group within the Q¹-Z— groupoptionally bears on each said CH₂ or CH₃ group one or more halogeno or(1-6C)alkyl substituents or a substituent selected from hydroxy, cyano,amino, carboxy, carbamoyl, (1-6C)alkoxy, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,(1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,or from a group of the formula:

—X⁷-Q⁸

[0118] wherein X⁷ is a direct bond or is selected from O, S, SO, SO₂,N(R¹⁴), CO, CH(OR¹⁴), CON(R¹⁴), N(R¹⁴)CO, SO₂N(R¹⁴), N(R¹⁴)SO₂,C(R¹⁴)₂O, C(R¹⁴)₂S and N(R¹⁴)C(R¹⁴)₂, wherein R¹⁴ is hydrogen or(1-6C)alkyl, and Q⁸ is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl,

[0119] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1, 2 or 3 substituents, which may be the same ordifferent, selected from halogeno, trifluoromethyl, cyano, nitro,hydroxy, amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl,(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,(2-6C)alkanoyloxy, (2-6C)alkanoylamino,N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl,N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino andN-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of theformula:

—X⁸—R¹⁵

[0120] wherein X⁸ is a direct bond or is selected from O and N(R¹⁶),wherein R¹⁶ is hydrogen or (1-6C)alkyl, and R¹⁵ is halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl,amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl ordi-[(1-6C)alkyl]amino-(1-6C)alkyl, or from a group of the formula:

—X⁹-Q⁹

[0121] wherein X⁹ is a direct bond or is selected from O and N(R¹⁷),wherein R¹⁷ is hydrogen or (1-6C)alkyl, and Q⁹ is aryl,aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from halogeno, (1-6C)alkyland (1-6C)alkoxy,

[0122] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo or thioxo substituents.

[0123] In this specification the generic term “alkyl” includes bothstraight-chain and branched-chain alkyl groups such as propyl, isopropyland tert-butyl, and (3-7C)cycloalkyl groups such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. However referencesto individual alkyl groups such as “propyl” are specific for thestraight-chain version only, references to individual branched-chainalkyl groups such as “isopropyl” are specific for the branched-chainversion only and references to individual cycloalkyl groups such as“cyclopentyl” are specific for that 5-membered ring only. An analogousconvention applies to other generic terms, for example (1-6C)alkoxyincludes methoxy, ethoxy, cyclopropyloxy and cyclopentyloxy,(1-6C)alkylamino includes methylamino, ethylamino, cyclobutylamino andcyclohexylamino, and di-[(1-6C)alkyl]amino includes dimethylamino,diethylamino, N-cyclobutyl-N-methylamino and N-cyclohexyl-N-ethylamino.

[0124] It is to be understood that, insofar as certain of the compoundsof Formula I defined above may exist in optically active or racemicforms by virtue of one or more asymmetric carbon atoms, the inventionincludes in its definition any such optically active or racemic formwhich possesses the above-mentioned activity. The synthesis of opticallyactive forms may be carried out by standard techniques of organicchemistry well known in the art, for example by synthesis from opticallyactive starting materials or by resolution of a racemic form. Similarly,the above-mentioned activity may be evaluated using the standardlaboratory techniques referred to hereinafter.

[0125] Suitable values for the generic radicals referred to aboveinclude those set out below.

[0126] A suitable value for any one of the ‘Q’ groups (Q¹, Q³ to Q¹⁰)when it is aryl or for the aryl group within a ‘Q’ group is, forexample, phenyl or naphthyl, preferably phenyl.

[0127] A suitable value for any one of the ‘Q’ groups (Q¹, Q³ to Q¹⁰)when it is (3-7C)cycloalkyl or for the (3-7C)cycloalkyl group within a‘Q’ group is, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl and a suitable value forany one of the ‘Q’ groups (Q¹, Q³ to Q⁸) when it is (3-7C)cycloalkenylor for the (3-7C)cycloalkenyl group within a ‘Q’ group is, for example,cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl.

[0128] A suitable value for any one of the ‘Q’ groups (Q¹, Q³ to Q¹⁰)when it is heteroaryl or for the heteroaryl group within a ‘Q’ group is,for example, an aromatic 5- or 6-membered monocyclic ring or a 9- or10-membered bicyclic ring with up to five ring heteroatoms selected fromoxygen, nitrogen and sulphur, for example furyl, pyrrolyl, thienyl,oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl,benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl,benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl,cinnolinyl or naphthyridinyl.

[0129] A suitable value for any one of the ‘Q’ groups (Q¹, Q³ to Q¹⁰)when it is heterocyclyl or for the heterocyclyl group within a ‘Q’ groupis, for example, a non-aromatic saturated or partially saturated 3 to 10membered monocyclic or bicyclic ring with up to five heteroatomsselected from oxygen, nitrogen and sulphur, for example oxiranyl,oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, pyrrolinyl,pyrrolidinyl, morpholinyl, tetrahydro, 1,4-thiazinyl,1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl,piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl,dihydropyrimidinyl or tetrahydropyriridinyl, preferablytetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl,1,1-dioxotetrahydro-4H-1,4-thiazinyl, piperidinyl or piperazinyl, morepreferably tetrahydrofuran-3-yl, tetrahydropyran-4-yl, pyrrolidin-3-yl,morpholino, 1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl, piperidino,piperidin-4-yl or piperazin-1-yl. A suitable value for such a groupwhich bears 1 or 2 oxo or thioxo substituents is, for example,2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl,2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl,2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.

[0130] A suitable value for a ‘Q’ group when it isheteroaryl-(1-6C)alkyl is, for example, heteroarylmethyl,2-heteroarylethyl and 3-heteroarylpropyl. The invention comprisescorresponding suitable values for ‘Q’ groups when, for example, ratherthan a heteroaryl-(1-6C)alkyl group, an aryl-(1-6C)alkyl,(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl-(1-6C)alkyl orheterocyclyl-(1-6C)alkyl group is present.

[0131] Suitable values for any of the ‘R’ groups (R¹ to R²⁰), or forvarious groups within an R¹ substituent, or for G¹ or for various groupswithin G¹, or for any of the ‘G’ groups (G² to G⁵) within Q², or forvarious groups within Q², or for Q¹ or for various groups within Q¹, orfor various groups within the Q¹-Z— group include: for halogeno fluoro,chloro, bromo and iodo; for (1-6C)alkyl: methyl, ethyl, propyl,isopropyl and tert-butyl; for (2-8C)alkenyl: vinyl, isopropenyl, allyland but-2-enyl; for (2-8C)alkynyl: ethynyl, 2-propynyl and but-2-ynyl;for (1-6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for(2-6C)alkenyloxy: vinyloxy and allyloxy; for (2-6C)alkynyloxy:ethynyloxy and 2-propynyloxy; for (1-6C)alkylthio: methylthio, ethylthioand propylthio; for (1-6C)alkylsulphinyl: methylsulphinyl andethylsulphinyl; for (1-6C)alkylsulphonyl: methylsulphonyl andethylsulphonyl; for (1-6C)alkylamino: methylamino, ethylamino,propylamino, isopropylamino and butylamino; for di-[(1-6C)alkyl]amino:dimethylamino, diethylamino, N-ethyl- N-methylamino anddiisopropylamino; for (1-6C)alkoxycarbonyl: methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl; forN-(1-6C)alkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl andN-propylcarbamoyl; for N,N-di-[(1-6C)alkyl]carbamoyl:N,N-dimethylcarbamoyl, N-ethyl- N-methylcarbamoyl andN,N-diethylcarbamoyl; for (2-6C)alkanoyl: acetyl and propionyl; for(2-6C)alkanoyloxy: acetoxy and propionyloxy; for (2-6C)alkanoylamino:acetamido and propionamido; for N-(1-6C)alkyl-(2-6C)alkanoylamino:N-methylacetamido and N-methylpropionamido; for N-(1-6C)alkylsulphamoyl:N-methylsulphamoyl and N-ethylsulphamoyl; forN,N-di-[(1-6C)alkyl]sulphamoyl: N,N-dimethylsulphamoyl; for(1-6C)alkanesulphonylamino: methanesulphonylamino andethanesulphonylamino; for N-(1-6C)alkyl-(1-6C)alkanesulphonylamino:N-methylmethanesulphonylamino and N-methylethanesulphonylamino; for(3-6C)alkenoylamino: acrylamido, methacrylamido and crotonamido; forN-(1-6C)alkyl-(3-6C)alkenoylamino: N-methylacrylamido andN-methylcrotonamido; for (3-6C)alkynoylamino: propiolamido; forN-(1-6C)alkyl-(3-6C)alkynoylamino: N-methylpropiolamido; foramino-(1-6C)alkyl: aminomethyl, 2-aminoethyl, 1-aminoethyl and3-aminopropyl; for (1-6C)alkylamino-(1-6C)alkyl: methylaminomethyl,ethylaminomethyl, 1-methylaminoethyl, 2-methylaminoethyl,2-ethylaminoethyl and 3-methylaminopropyl; fordi-[(1-6C)alkyl]amino-(1-6C)alkyl: dimethylaminomethyl,diethylaminomethyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl and3-dimethylaminopropyl; for halogeno-(1-6C)alkyl: chloromethyl,2-chloroethyl, 1-chloroethyl and 3-chloropropyl; forhydroxy-(1-6C)alkyl: hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and3-hydroxypropyl; for (1-6C)alkoxy-(1-6C)alkyl: methoxymethyl,ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and3-methoxypropyl; for cyano-(1-6C)alkyl: cyanomethyl, 2-cyanoethyl,1-cyanoethyl and 3-cyanopropyl; for (2-6C)alkanoylamino-(1-6C)alkyl:acetamidomethyl, propionamidomethyl and 2-acetamidoethyl; and for(1-6C)alkoxycarbonylamino-(1-6C)alkyl: methoxycarbonylaminomethyl,ethoxycarbonylaminomethyl, tert-butoxycarbonylaminomethyl and2-methoxycarbonylaminoethyl.

[0132] A suitable value for (R¹)_(m) when it is a (1-3C)alkylenedioxygroup is, for example, methylenedioxy or ethylenedioxy and the oxygenatoms thereof occupy adjacent ring positions.

[0133] When, as defined hereinbefore, an R¹ group forms a group of theformula Q³-X¹— and, for example, X¹ is a OC(R⁴)₂ linking group, it isthe carbon atom, not the oxygen atom, of the OC(R⁴)₂ linking group whichis attached to the quinazoline ring and the oxygen atom is attached tothe Q³ group. Similarly, when, for example a CH₃ group within a R¹substituent bears a group of the formula —X³-Q⁵ and, for example, X³ isa C(R⁷)₂O linking group, it is the carbon atom, not the oxygen atom, ofthe C(R⁷)₂O linking group which is attached to the CH₃ group and theoxygen atom is linked to the Q⁵ group. A similar convention applies tothe attachment of the groups of the formulae Q⁴-X²— and —X⁷-Q⁷.

[0134] As defined hereinbefore, adjacent carbon atoms in any(2-6C)alkylene chain within a R¹ substituent may be optionally separatedby the insertion into the chain of a group such as O, CON(R⁵) or C≡C.For example, insertion of a C≡C group into the ethylene chain within a2-morpholinoethoxy group gives rise to a 4-morpholinobut-2-ynyloxy groupand, for example, insertion of a CONH group into the ethylene chainwithin a 3-methoxypropoxy group gives rise to, for example, a2-(2-methoxyacetamido)ethoxy group.

[0135] When, as defined hereinbefore, any CH₂═CH— or HC≡C— group withina R¹ substituent optionally bears at the terminal CH₂═ or HC— position asubstituent such as a group of the formula Q⁴-X²— wherein X² is, forexample, NHCO and Q⁴ is a heterocyclyl-(1-6C)alkyl group, suitable R¹substituents so formed include, for example,N-[heterocyclyl-(1-6C)alkyl]carbamoylvinyl groups such asN-(2-pyrrolidin-1-ylethyl)carbamoylvinyl orN-[heterocyclyl-(1-6C)alkyl]carbamoylethynyl groups such asN-(2-pyrrolidin-1-ylethyl)carbamoylethynyl.

[0136] When, as defined hereinbefore, any CH₂ or CH₃ group within a R¹substituent optionally bears on each said CH₂ or CH₃ group one or morehalogeno or (1-6C)alkyl substituents, there are suitably 1 or 2 halogenoor (1-6C)alkyl substituents present on each said CH₂ group and there aresuitably 1, 2 or 3 such substituents present on each said CH₃ group.

[0137] When, as defined hereinbefore, any CH₂ or CH₃ group within a R¹substituent optionally bears on each said CH₂ or CH₃ group a substituentas defined hereinbefore, suitable R¹ substituents so formed include, forexample, hydroxy-substituted heterocyclyl-(1-6C)alkoxy groups such as2-hydroxy-3-piperidinopropoxy and 2-hydroxy-3-morpholinopropoxy,hydroxy-substituted amino-(2-6C)alkoxy groups such as3-amino-2-hydroxypropoxy, hydroxy-substituted(1-6C)alkylamino-(2-6C)alkoxy groups such as2-hydroxy-3-methylaminopropoxy, hydroxy-substituteddi-[(1-6C)alkyl]amino-(2-6C)alkoxy groups such as3-dimethylamino-2-hydroxypropoxy, hydroxy-substitutedheterocyclyl-(1-6C)alkylamino groups such as2-hydroxy-3-piperidinopropylamino and 2-hydroxy-3-morpholinopropylamino,hydroxy-substituted amino-(2-6C)alkylamino groups such as3-amino-2-hydroxypropylamino, hydroxy-substituted(1-6C)alkylamino-(2-6C)alkylamino groups such as2-hydroxy-3-methylaminopropylanmino, hydroxy-substituteddi-[(1-6C)alkyl]amino-(2-6C)alkylamino groups such as3-dimethylamino-2-hydroxypropylamino, hydroxy-substituted (1-6C)alkoxygroups such as 2-hydroxyethoxy, (1-6C)alkoxy-substituted (1-6C)alkoxygroups such as 2-methoxyethoxy and 3-ethoxypropoxy,(1-6C)alkylsulphonyl-substituted (1-6C)alkoxy groups such as2-methylsulphonylethoxy and heterocyclyl-substituted(1-6C)alkylamino-(1-6C)alkyl groups such as2-morpholinoethylaminomethyl, 2-piperazin-1-ylethylaminomethyl and3-morpholinopropylaminomethyl.

[0138] Similar considerations apply to the attachments and substitutionswithin the —Z-Q¹ group.

[0139] When, as defined hereinbefore, G¹ and G² together form, forexample, a group of formula —O—CH═CH—, it is the oxygen atom, not thecarbon atom, which is attached to the ortho-position of the phenyl ringof formula Ia and the carbon atom is attached to the adjacentmeta-position of the phenyl ring of formula Ia. Similarly, when, forexample, G² and G³ together form, for example, a group of formula—CH═CH—CH═N—, it is the carbon atom, not the nitrogen atom, which isattached to the G² meta-position of the phenyl ring of formula Ia andthe nitrogen atom is attached to the adjacent G³ para-position of thephenyl ring of formula Ia. A similar convention applies to theattachment of the groups when, for example, G³ and G⁴ are joined.

[0140] A suitable pharmaceutically-acceptable salt of a compound of theFormula I is, for example, an acid-addition salt of a compound of theFormula I, for example an acid-addition salt with an inorganic ororganic acid such as hydrochloric, hydrobromic, sulphuric,trifluoroacetic, citric or maleic acid; or, for example, a salt of acompound of the Formula I which is sufficiently acidic, for example analkali or alkaline earth metal salt such as a calcium or magnesium salt,or an ammonium salt, or a salt with an organic base such as methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

[0141] Particular novel compounds of the invention include, for example,quinazoline derivatives of the Formula I, or pharmaceutically-acceptablesalts thereof, wherein, unless otherwise stated, each of m, R¹, R², R³,Z, Q¹ and Q² has any of the meanings defined hereinbefore or inparagraphs (a) to (ee) hereinafter:

[0142] (a) m is 1 or 2, and each R¹ group, which may be the same ordifferent, is selected from halogeno, trifluoromethyl, hydroxy, amino,carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy,(1-6C)alkylamino, di-[(1-6C)alkyl] amino, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoylamino,N-(1-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino,N-(1-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino andN-(1-6C)alkyl-(3-6C)alkynoylamino, or from a group of the formula:

Q³-X¹—

[0143] wherein X¹ is a direct bond or is selected from O, N(R⁴),CON(R⁴), N(R⁴)CO and OC(R⁴)₂ wherein R⁴ is hydrogen or (1-6C)alkyl, andQ³ is aryl, aryl-(1-6C)alkyl, cycloalkyl-(1-6C)alkyl, heteroaryl,heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,

[0144] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin a R¹ substituent are optionally separated by the insertion intothe chain of a group selected from O, N(R⁵), CON(R⁵), N(R⁵)CO, CH═CH andC≡C wherein R⁵ is hydrogen or (1-6C)alkyl,

[0145] and wherein any CH₂═CH— or HC≡C— group within a R¹ substituentoptionally bears at the terminal CH₂═ or HC≡ position a substituentselected from carbamoyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl orfrom a group of the formula:

Q⁴-X²—

[0146] wherein X² is a direct bond or is CO or N(R⁶)CO, wherein R ishydrogen or (1-6C)alkyl, and Q⁴ is heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl,

[0147] and wherein any CH₂ or CH₃ group within a R¹ substituentoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylsulphonyl,(1-6C)alkylamino and di-[(1-6C)alkyl]amino, or from a group of theformula:

—X³-Q⁵

[0148] wherein X³ is a direct bond or is selected from O, N(R⁷),CON(R⁷), N(R⁷)CO and C(R⁷)₂O, wherein R⁷ is hydrogen or (1-6C)alkyl, andQ⁵ is heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl,

[0149] and wherein any aryl, heteroaryl or heterocyclyl group within asubstituent on R¹ optionally bears 1, 2 or 3 substituents, which may bethe same or different, selected from halogeno, trifluoromethyl, hydroxy,amino, carbamoyl, (1-6C)alkyl, (1-6C)alkoxy, N-(1-6C)alkylcarbamoyl andN,N-di-[(1-6C)alkyl]carbamoyl, or optionally bears 1 substituentselected from a group of the formula:

—X⁴—R⁸

[0150] wherein X⁴ is a direct bond or is selected from O and N(R⁹),wherein R⁹ is hydrogen or (1-6C)alkyl, and R⁸ is hydroxy-(1-6C)alkyl,(1-6C)alkoxy-(1-6C)alkyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl,(2-6C)alkanoylamino-(1-6C)alkyl or(1-6C)alkoxycarbonylamino-(1-6C)alkyl, and from a group of the formula:

—X⁵-Q⁶

[0151] wherein X⁵ is a direct bond or is selected from O and N(R¹⁰),wherein R¹⁰ is hydrogen or (1-6C)alkyl, and Q⁶ is heterocyclyl orheterocyclyl-(1-6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from halogeno, (1-6C)alkyland (1-6C)alkoxy,

[0152] and wherein any heterocyclyl group within a substituent on R¹optionally bears 1 or 2 oxo substituents;

[0153] (b) m is 1 or 2, and each R¹ group, which may be the same ordifferent, is selected from fluoro, chloro, trifluoromethyl, hydroxy,amino, carbamoyl, methyl, ethyl, propyl, vinyl, ethynyl, methoxy,ethoxy, propoxy, methylamino, ethylamino, propylamino, dimethylamino,diethylamino, dipropylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl,acetamido, propionamido, acrylamido and propiolamido, or from a group ofthe formula:

Q³-X¹—

[0154] wherein X¹ is a direct bond or is selected from O, NH, CONH, NHCOand OCH₂ and Q³ is phenyl, benzyl, cyclopropylmethyl, 2-thienyl,1-imidazolyl, 1,2,3-triazol-1-yl, 2-, 3- or 4-pyridyl,2-imidazol-1-ylethyl, 3-imidazol-1-ylpropyl, 2-(1,2,3-triazolyl)ethyl,3-(1,2,3-triazolyl)propyl, 2-, 3- or 4-pyridylmethyl, 2-(2-, 3- or4-pyridyl)ethyl, 3-(2-, 3- or 4-pyridyl)propyl, 1-, 2- or3-pyrrolidinyl, morpholino, 1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl,piperidino, piperidin-3-yl, piperidin-4-yl, 1-, 3- or 4-homopiperidinyl,piperazin-1-yl, homopiperazin-1-yl, 1-, 2- or 3-pyrrolidinylmethyl,morpholinomethyl, piperidinomethyl, 3- or 4-piperidinylmethyl, 1-, 3- or4-homopiperidinylmethyl, 2-pyrrolidin-1-ylethyl,3-pyrrolidin-2-ylpropyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl,3-pyrrolidin-1-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl,2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethyl,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propyl, 2-piperidinoethyl,3-piperidinopropyl, 2-piperidin-3-ylethyl, 2-piperidin-4-ylethyl,2-homopiperidin-1-ylethyl, 3-homopiperidin-1-ylpropyl,2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl, 2-homopiperazin-1-ylethylor 3-homopiperazin-1-ylpropyl,

[0155] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin a R¹ substituent are optionally separated by the insertion intothe chain of a group selected from O, NH, CONH, NHCO, CH═CH and C≡C,

[0156] and wherein any CH₂═CH— or HC≡C— group within a R¹ substituentoptionally bears at the terminal CH₂═ or HC— position a substituentselected from carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl,N-propylcarbamoyl, N,N-dimethylcarbamoyl, aminomethyl, 2-aminoethyl,3-aminopropyl, 4-aminobutyl, methylaminomethyl, 2-methylaminoethyl,3-methylaminopropyl, 4-methylaminobutyl, dimethylaminomethyl,2-dimethylaminoethyl, 3-dimethylaminopropyl or 4-dimethylaminobutyl, orfrom a group of the formula:

Q⁴-X²—

[0157] wherein X² is a direct bond or is CO, NHCO or N(Me)CO and Q⁴ ispyridyl, pyridylmethyl, 2-pyridylethyl, pyrrolidin-1-yl,pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidin-4-yl,piperazin-1-yl, pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl,3-pyrrolidin-1-ylpropyl, 4-pyrrolidin-1-ylbutyl, pyrrolidin-2-ylmethyl,2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, morpholinomethyl,2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl,piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl,4-piperidinobutyl, piperidin-3-ylmethyl, 2-piperidin-3-ylethyl,piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, piperazin-1-ylmethyl,2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl or 4-piperazin-1-ylbutyl,

[0158] and wherein any CH₂ or CH₃ group within a R¹ substituentoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, methoxy, methylsulphonyl, methylamino anddimethylamino, or from a group of the formula:

—X³-Q⁵

[0159] wherein X³ is a direct bond or is selected from O, NH, CONH, NHCOand CH₂O and Q⁵ is pyridyl, pyridylmethyl, pyrrolidin-1-yl,pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidin-4-yl,piperazin-1-yl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl,pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl,2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl,3-piperidinopropyl, piperidin-3-ylmethyl, 2-piperidin-3-ylethyl,piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, 2-piperazin-1-ylethyl or3-piperazin-1-ylpropyl,

[0160] and wherein any aryl, heteroaryl or heterocyclyl group within asubstituent on R¹ optionally bears 1, 2 or 3 substituents, which may bethe same or different, selected from fluoro, chloro, trifluoromethyl,hydroxy, amino, carbamoyl, methyl, ethyl and methoxy, or optionallybears 1 substituent selected from a group of the formula:

—X⁴—R⁸

[0161] wherein X⁴ is a direct bond or is selected from O and NH and R⁸is 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl,aminomethyl, 2-aminoethyl, 3-aminopropyl, methylaminomethyl,2-methylaminoethyl, 3-methylaminopropyl, 2-ethylaminoethyl,3-ethylaminopropyl, dimethylaminomethyl, 2-dimethylaminoethyl,3-dimethylaminopropyl, acetamidomethyl, methoxycarbonylaminomethyl,ethoxycarbonylaminomethyl or tert-butoxycarbonylaminomethyl, and from agroup of the formula:

—X⁵-Q⁶

[0162] wherein X⁵ is a direct bond or is selected from O and NH and Q⁶is pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl,3-pyrrolidin-1-ylpropyl, morpholinomethyl, 2-morpholinoethyl,3-morpholinopropyl, piperidinomethyl, 2-piperidinoethyl,3-piperidinopropyl, piperazin-1-ylmethyl, 2-piperazin-1-ylethyl or3-piperazin-1-ylpropyl, each of which optionally bears 1 or 2substituents, which may be the same or different, selected from fluoro,chloro, methyl and methoxy,

[0163] and wherein any heterocyclyl group within a substituent on R¹optionally bears 1 or 2 oxo substituents;

[0164] (c) m is 1 or 2 and the R¹ groups, which may be the same ordifferent, are located at the 6- and/or 7-positions and are selectedfrom hydroxy, amino, methyl, ethyl, propyl, vinyl, ethynyl, methoxy,ethoxy, propoxy, methylamino, ethylamino, dimethylamino, diethylamino,acetamido, propionamido, benzyloxy, cyclopropylmethoxy,2-imidazol-1-ylethoxy, 3-imidazol-1-ylpropoxy,2-(1,2,3-triazol-1-yl)ethoxy, 3-(1,2,3-triazol-1-yl)propoxy,pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, pyrid-4-ylmethoxy,2-pyrid-2-ylethoxy, 2-pyrid-3-ylethoxy, 2-pyrid-4-ylethoxy,3-pyrid-2-ylpropoxy, 3-pyrid-3-ylpropoxy, 3-pyrid-4-ylpropoxy,pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy,pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy,3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy,piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy,2-piperidin-4-ylethoxy, 2-homopiperidin-1-ylethoxy,3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-homopiperazin-1-ylethoxy,3-homopiperazin-1-ylpropoxy, 2-pyrrolidin-1-ylethylamino,3-pyrrolidin-1-ylpropylamino, pyrrolidin-3-ylamino,pyrrolidin-2-ylmethylamino, 2-pyrrolidin-2-ylethylamino,3-pyrrolidin-2-ylpropylamino, 2-morpholinoethylamino,3-morpholinopropylamino,2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethylamino,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propylamino,2-piperidinoethylamino, 3-piperidinopropylamino, piperidin-3-ylamino,piperidin-4-ylamino, piperidin-3-ylmethylamino,2-piperidin-3-ylethylamino, piperidin-4-ylmethylamino,2-piperidin-4-ylethylamino, 2-homopiperidin-1-ylethylamino,3-homopiperidin-1-ylpropylamino, 2-piperazin-1-ylethylamino,3-piperazin-1-ylpropylamino, 2-homopiperazin-1-ylethylamino or3-homopiperazin-1-ylpropylamino,

[0165] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin a R¹ substituent are optionally separated by the insertion intothe chain of a group selected from O, NH, CH═CH and C≡C,

[0166] and when R¹ is a vinyl or ethynyl group, the R¹ substituentoptionally bears at the terminal CH₂═ or HC≡ position a substituentselected from N-(2-dimethylaminoethyl)carbamoyl,N-(3-dimethylaminopropyl)carbamoyl, methylaminomethyl,2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl,dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl and4-dimethylaminobutyl, or from a group of the formula:

Q⁴-X²—

[0167] wherein X² is a direct bond or is NHCO or N(Me)CO and Q⁴ isimidazolylmethyl, 2-imidazolylethyl, 3-imidazolylpropyl, pyridylmethyl,2-pyridylethyl, 3-pyridylpropyl, pyrrolidin-1-ylmethyl,2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 4-pyrrolidin-1-ylbutyl,pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl,morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl,4-morpholinobutyl, piperidinomethyl, 2-piperidinoethyl,3-piperidinopropyl, 4-piperidinobutyl, piperidin-3-ylmethyl,2-piperidin-3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl,piperazin-1-ylmethyl, 2-piperazin-1-ylethyl, 3-piperazin-1-ylpropylor4-piperazin-1-ylbutyl,

[0168] and wherein any CH₂ or CH₃ group within a R¹ substituentoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, methoxy, methylsulphonyl, methylamino anddimethylamino,

[0169] and wherein any phenyl, pyridyl or heterocyclyl group within asubstituent on R¹ optionally bears 1 or 2 substituents, which may be thesame or different, selected from fluoro, chloro, trifluoromethyl,hydroxy, amino, carbamoyl, methyl, ethyl and methoxy, and apiperidin-3-ylmethyl or piperidin-4-ylmethyl group within a R¹substituent is optionally N-substituted with 2-methoxyethyl,3-methoxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl,3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl,2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 2-morpholinoethyl,3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl, the last 8 of whichsubstituents each optionally bears 1 or 2 substituents, which may be thesame or different, selected from fluoro, chloro, methyl and methoxy,

[0170] and wherein any heterocyclyl group within a substituent on R¹optionally bears 1 or 2 oxo substituents;

[0171] (d) m is 1 and the R¹ group is located at the 6- or 7-positionand is selected from hydroxy, amino, methyl, ethyl, propyl, methoxy,ethoxy, propoxy, methylamino, ethylamino, dimethylamino, diethylamino,acetamido, propionamido, benzyloxy, 2-imidazol-1-ylethoxy,2-(1,2,4-triazol-1-yl)ethoxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy,piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy,2-piperidin-4-ylethoxy, 2-homopiperidin-1-ylethoxy,3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-homopiperazin-1-ylethoxy or3-homopiperazin-1-ylpropoxy,

[0172] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin a R¹ substituent are optionally separated by the insertion intothe chain of a group selected from O, NH, CH═CH and C≡C,

[0173] and wherein any CH₂ or CH₃ group within a R¹ substituentoptionally bears on each said CH₂ or CH₃ group a subsitituent selectedfrom hydroxy, amino, methoxy, methylsulphonyl, methylamino anddimethylamino,

[0174] and wherein any phenyl or heterocyclyl group within a substituenton R¹ optionally bears 1 or 2 substituents, which may be the same ordifferent, selected from fluoro, chloro, trifluoromethyl, hydroxy,amino, methyl, ethyl and methoxy,

[0175] and wherein any heterocyclyl group within a substituent on R¹optionally bears 1 or 2 oxo substituents;

[0176] (e) m is 0;

[0177] (f) R² is hydrogen;

[0178] (g) R³ is hydrogen;

[0179] (h) Z is a direct bond or is selected from O, S, SO, SO₂, N(R¹¹)and CO;

[0180] (i) Z is selected from CON(R¹¹), N(R¹¹)CO, SO₂N(R¹¹), N(R¹¹)SO₂,OC(R¹¹)₂, SC(R¹¹)₂ and N(R¹¹)C(R¹¹)₂, wherein R¹¹ is hydrogen or(1-6C)alkyl;

[0181] (j) the Q¹-Z— group is selected from (1-6C)alkyl, (2-8C)alkenyl,(2-8C)alkynyl, (1-6C)alkoxy, (2-8C)alkenyloxy, (2-8C)alkynyloxy,halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl,cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, halogeno-(1-6C)alkoxy,hydroxy-(1-6C)alkoxy, (1-6C)alkoxy-(1-6C)alkoxy, cyano-(1-6C)alkoxy,amino-(1-6C)alkoxy, (1-6C)alkylamino-(1-6C)alkoxy anddi-[(1-6C)alkyl]amino-(1-6C)alkoxy,

[0182] or Z is a direct bond or is selected from O, S, SO, SO₂, N(R¹¹)and CO wherein R¹¹ is hydrogen or (1-6C)alkyl, and Q¹ is aryl,aryl-(1-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl,heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl,

[0183] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin the Q¹-Z— group are optionally separated by the insertion intothe chain of a group selected from O, N(R¹²), CON(R¹²), N(R¹²)CO, CH═CHand C≡C wherein R¹² is hydrogen or (1-6C)alkyl,

[0184] and wherein any CH₂═CH— or HC≡C— group within the Q¹-Z— groupoptionally bears at the terminal CH₂═ or HC≡ position a substituentselected from carbamoyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl orfrom a group of the formula:

Q⁷-X^(6—)

[0185] wherein X⁶ is a direct bond or is CO or N(R¹³)CO, wherein R¹³ ishydrogen or (1-6C)alkyl, and Q⁷ is heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl,

[0186] and wherein any CH₂ or CH₃ group within the Q¹-Z— groupoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylsulphonyl,(1-6C)alkylamino and di-[(1-6C)alkyl]amino, or from a group of theformula:

—X⁷-Q⁸

[0187] wherein X⁷ is a direct bond or is selected from O, N(R¹⁴),CON(R¹⁴), N(R¹⁴)CO and C(R¹⁴)₂O, wherein R¹⁴ is hydrogen or (1-6C)alkyl,and Q⁸ is heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl,

[0188] and wherein any aryl, heteroaryl or heterocyclyl group within theQ¹-Z— group optionally bears 1, 2 or 3 substituents, which may be thesame or different, selected from halogeno, trifluoromethyl, hydroxy,amino, carbamoyl, (1-6C)alkyl, (1-6C)alkoxy, N-(1-6C)alkylcarbamoyl andN,N-di-[(1-6C)alkyl]carbamoyl, or optionally bears 1 substituentselected from a group of the formula:

—X⁸—R¹⁵

[0189] wherein X⁴ is a direct bond or is selected from O and N(R¹⁶),wherein R¹⁶ is hydrogen or (1-6C)alkyl, and R¹⁵ is hydroxy-(1-6C)alkyl,(1-6C)alkoxy-(1-6C)alkyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl,(2-6C)alkanoylamino-(1-6C)alkyl or(1-6C)alkoxycarbonylamino-(1-6C)alkyl, and a group of the formula:

—X⁹-Q⁹

[0190] wherein X⁹ is a direct bond or is selected from O and N(R¹⁷),wherein R¹⁷ is hydrogen or (1-6C)alkyl, and Q⁹ is heterocyclyl orheterocyclyl-(1-6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from halogeno, (1-6C)alkyland (1-6C)alkoxy,

[0191] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo substituents;

[0192] (k) the Q¹-Z— group is selected from methoxy, ethoxy, propoxy,isopropoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy,3-methoxypropoxy, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy,3-methylaminopropoxy, 2-ethylaminoethoxy, 3-ethylaminopropoxy,2-dimethylaminoethoxy, 3-dimethylaminopropoxy, cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy,cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy,cyclohexylmethoxy and cycloheptylmethoxy,

[0193] or Z is a direct bond or is selected from O, S, SO, SO₂ and NHand Q¹ is phenyl, benzyl, 2-thienyl, 1-imidazolyl, 1,2,3-triazol-1-yl,1,2,4-triazol-1-yl, 2-, 3- or 4-pyridyl, 2-imidazol-1-ylethyl,3-imidazol-1-ylpropyl, 2-(1,2,3-triazol-1-yl)ethyl,2-(1,2,4-triazol-1-yl)ethyl, 3-(1,2,3-triazol-1-yl)propyl,3-(1,2,4-triazol-1-yl)propyl, 2-, 3- or 4-pyridylmethyl, 2-(2-, 3- or4-pyridyl)ethyl, 3-(2-, 3- or 4-pyridyl)propyl, oxetan-3-yl,tetrahydrofuran-3-yl, 3- or 4-tetrahydropyranyl, 3- or 4-oxepanyl, 1-,2- or 3-pyrrolidinyl, morpholino,1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl, piperidino, piperidin-3-yl,piperidin-4-yl, 1-, 3- or 4-homopiperidinyl, piperazin-1-yl,homopiperazin-1-yl, 1-, 2- or 3-pyrrolidinylmethyl, morpholinomethyl,piperidinomethyl, 3- or 4-piperidinylmethyl, 1-, 3- or4-homopiperidinylmethyl, 2-pyrrolidin-1-ylethyl,3-pyrrolidin-1-ylpropyl, 2-pyrrolidin-2-ylethyl,3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl,2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethyl,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propyl, 2-piperidinoethyl,3-piperidinopropyl, 2-piperidin-3-ylethyl, 2-piperidin-4-ylethyl,2-homopiperidin-1-ylethyl, 3-homopiperidin-1-ylpropyl,2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl, 2-homopiperazin-1-ylethylor 3-homopiperazin-1-ylpropyl,

[0194] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin the Q¹-Z— group are optionally separated by the insertion intothe chain of a group selected from O, NH, CONH, NHCO, CH═CH and C≡C,

[0195] and wherein any CH₂ or CH₃ group within the Q¹-Z— groupoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, methoxy, methylsulphonyl, methylamino anddimethylamino, or from a group of the formula:

—X⁷-Q⁸

[0196] wherein X⁷ is a direct bond or is selected from O, NH, CONH, NHCOand CH₂O and Q⁸ is pyridyl, pyridylmethyl, pyrrolidin-1-yl,pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidin-4-yl,piperazin-1-yl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl,pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl,2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl,3-piperidinopropyl, piperidin-3-ylmethyl, 2-piperidin-3-ylethyl,piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, 2-piperazin-1-ylethyl or3-piperazin-1-ylpropyl,

[0197] and wherein any aryl, heteroaryl or heterocyclyl group within theQ¹-Z— group optionally bears 1, 2 or 3 substituents, which may be thesame or different, selected from fluoro, chloro, trifluoromethyl,hydroxy, amino, carbamoyl, methyl, ethyl and methoxy, or optionallybears 1 substituent selected from a group of the formula:

—X⁸—R¹⁵

[0198] wherein X⁵ is a direct bond or is selected from O and NH and R¹⁵is 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl,aminomethyl, 2-aminoethyl, 3-aminopropyl, methylaminomethyl,2-methylaminoethyl, 3-methylaminopropyl, 2-ethylaminoethyl,3-ethylaminopropyl, dimethylaminomethyl, 2-dimethylaminoethyl,3-dimethylaminopropyl, acetamidomethyl, methoxycarbonylaminomethyl,ethoxycarbonylaminomethyl or tert-butoxycarbonylaminomethyl, and from agroup of the formula:

—X⁹-Q⁹

[0199] wherein X⁹ is a direct bond or is selected from O and NH and Q⁹is pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl,3-pyrrolidin-1-ylpropyl, morpholinomethyl, 2-morpholinoethyl,3-morpholinopropyl, piperidinomethyl, 2-piperidinoethyl,3-piperidinopropyl, piperazin-1-ylmethyl, 2-piperazin-1-ylethyl or3-piperazin-1-ylpropyl, each of which optionally bears 1 or 2substituents, which may be the same or different, selected from fluoro,chloro, methyl and methoxy,

[0200] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo substituents;

[0201] (1) the Q¹-Z— group is selected from methoxy, ethoxy, propoxy,isopropoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy,3-methoxypropoxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy,cycloheptyloxy, phenoxy, phenylthio, anilino, benzyloxy,cyclopropylmethoxy, tetrahydrofuran-3-yloxy, 3- or4-tetrahydropyranyloxy, 2-imidazol-1-ylethoxy, 3-imidazol-1-ylpropoxy,2-(1,2,3-triazol-1-yl)ethoxy, 2-(1,2,4-triazol-1-yl)ethoxy,3-(1,2,3-triazol-1-yl)propoxy, 3-(1,2,4-triazol-1-yl)propoxy,pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy,pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy,3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy,piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy,2-piperidin-4-ylethoxy, homopiperidin-3-yloxy, homopiperidin-4-yloxy,homopiperidin-3-ylmethoxy, 2-homopiperidin-1-ylethoxy,3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-homopiperazin-1-ylethoxy,3-homopiperazin-1-ylpropoxy, 2-pyrrolidin-1-ylethylamino,3-pyrrolidin-1-ylpropylamino, pyrrolidin-3-ylamino,pyrrolidin-2-ylmethylamino, 2-pyrrolidin-2-ylethylamino,3-pyrrolidin-2-ylpropylamino, 2-morpholinoethylamino,3-morpholinopropylamino,2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethylamino,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propylamino,2-piperidinoethylamino, 3-piperidinopropylamino, piperidin-3-ylamino,piperidin-4-ylamino, piperidin-3-ylmethylamino,2-piperidin-3-ylethylamino, piperidin-4-ylmethylamino,2-piperidin-4-ylethylamino, homopiperidin-3-ylamino,homopiperidin-4-ylamino, homopiperidin-3-ylmethylamino,2-homopiperidin-1-ylethylamino, 3-homopiperidin-1-ylpropylamino,2-piperazin-1-ylethylamino, 3-piperazin-1-ylpropylamino,2-homopiperazin-1-ylethylamino or 3-homopiperazin-1-ylpropylamino,

[0202] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin the Q¹-Z— group are optionally separated by the insertion intothe chain of a group selected from O, NH, CH═CH and C≡C,

[0203] and wherein any CH₂ or CH₃ group within the Q¹-Z— groupoptionally bears on each said CH, or CH₃ group a substituent selectedfrom hydroxy, amino, methoxy, methylsulphonyl, methylamino anddimethylamino,

[0204] and wherein any phenyl or heterocyclyl group within the Q¹-Zgroup optionally bears 1 or 2 substituents, which may be the same ordifferent, selected from fluoro, chloro, trifluoromethyl, hydroxy,amino, carbamoyl, methyl, ethyl and methoxy, and a piperidin-3-ylmethylor piperidin-4-ylmethyl group within the Q¹-Z— group is optionallyN-substituted with 2-methoxyethyl, 3-methoxypropyl, 2-aminoethyl,3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl,2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-pyrrolidin-1-ylethyl,3-pyrrolidin-1-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl,2-piperidinoethyl, 3-piperidinopropyl, 2-piperazin-1-ylethyl or3-piperazin-1-ylpropyl, the last 8 of which substituents each optionallybears 1 or 2 substituents, which may be the same or different, selectedfrom fluoro, chloro, methyl and methoxy,

[0205] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo substituents;

[0206] (m) the Q¹-Z— group is selected from propoxy, isopropoxy,2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 3-methoxypropoxy,cyclopentyloxy, cyclohexyloxy, phenoxy, benzyloxy,tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,tetrahydropyran-4-yloxy, 2-imidazol-1-ylethoxy,2-(1,2,4-triazol-1-yl)ethoxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy,piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy,2-piperidin-4-ylethoxy, 2-homopiperidin-1-ylethoxy,3-homopiperidin-1-ylpropoxy, homopiperidin-3-yloxy,homopiperidin-4-yloxy, homopiperidin-3-ylmethoxy,2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy,2-homopiperazin-1-ylethoxy or 3-homopiperazin-1-ylpropoxy,

[0207] and wherein any CH₂ or CH₃ group within the Q¹-Z— groupoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, methoxy, methylsulphonyl, methylamino anddimethylamino,

[0208] and wherein any phenyl or heterocyclyl group within the Q¹-Z—group optionally bears 1 or 2 substituents, which may be the same ordifferent, selected from fluoro, chloro, trifluoromethyl, hydroxy,amino, methyl, ethyl and methoxy,

[0209] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo substituents;

[0210] (n) Z is a direct bond or is selected from O, S, SO, SO₂, N(R¹¹)and CO wherein R¹¹ is hydrogen or (1-6C)alkyl, and Q¹ is aryl,aryl-(1-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl,heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl,

[0211] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin the Q¹-Z— group are optionally separated by the insertion intothe chain of a group selected from O, N(R¹²), CON(R¹²), N(R¹²)CO, CH═CHand C≡C wherein R¹² is hydrogen or (1-6C)alkyl,

[0212] and wherein any CH₂═CH— or HC≡C— group within the Q¹-Z— groupoptionally bears at the terminal CH₂═ or CH₃ position a substituentselected from carbamoyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl orfrom a group of the formula:

Q⁷-X⁶—

[0213] wherein X⁶ is a direct bond or is CO or N(R¹³)CO, wherein R¹³ ishydrogen or (1-6C)alkyl, and Q⁷ is heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl,

[0214] and wherein any CH₂ or CH₃ group within the Q¹-Z— groupoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylsulphonyl,(1-6C)alkylamino and di-[(1-6C)alkyl]amino, or from a group of theformula:

—X⁷-Q⁸

[0215] wherein X⁷ is a direct bond or is selected from O, N(R¹⁴),CON(R¹⁴), N(R¹⁴)CO and C(R¹⁴)₂O, wherein R¹⁴ is hydrogen or (1-6C)alkyl,and Q⁸ is heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl,

[0216] and wherein any aryl, heteroaryl or heterocyclyl group within theQ¹-Z— group optionally bears 1, 2 or 3 substituents, which may be thesame or different, selected from halogeno, trifluoromethyl, hydroxy,amino, carbamoyl, (1-6C)alkyl, (1-6C)alkoxy, N-(1-6C)alkylcarbamoyl andN,N-di-[(1-6C)alkyl]carbamoyl, or optionally bears 1 substituentselected from a group of the formula:

—X⁸—R¹⁵

[0217] wherein X⁴ is a direct bond or is selected from O and N(R⁶),wherein R¹⁶ is hydrogen or (1-6C)alkyl, and R¹⁵ is hydroxy-(1-6C)alkyl,(1-6C)alkoxy-(1-6C)alkyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl,(2-6C)alkanoylamino-(1-6C)alkyl or(1-6C)alkoxycarbonylamino-(1-6C)alkyl, and a group of the formula:

—X⁹-Q⁹

[0218] wherein X⁹ is a direct bond or is selected from O and N(R¹⁷),wherein R¹⁷ is hydrogen or (1-6C)alkyl, and Q⁹ is heterocyclyl orheterocyclyl-(1-6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from halogeno, (1-6C)alkyland (1-6C)alkoxy,

[0219] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo substituents;

[0220] (o) Z is a direct bond or is selected from O, S, SO, SO₂ and NHand Q¹ is phenyl, benzyl, 2-thienyl, 1-imidazolyl, 1,2,3-triazol-1-yl,1,2,4-triazol-1-yl, 2-, 3- or 4-pyridyl, 2-imidazol-1-ylethyl,3-imidazol-1-ylpropyl, 2-(1,2,3-triazol-1-yl)ethyl,2-(1,2,4-triazol-1-yl)ethyl, 3-(1,2,3-triazol-1-yl)propyl,3-(1,2,4-triazol-1-yl)propyl, 2-, 3- or 4-pyridylmethyl, 2-(2-, 3- or4-pyridyl)ethyl, 3-(2-, 3- or 4-pyridyl)propyl, oxetan-3-yl,tetrahydrofuran-3-yl, 3- or 4-tetrahydropyranyl, 3- or 4-oxepanyl, 1-,2- or 3-pyrrolidinyl, morpholino,1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl, piperidino, piperidin-3-yl,piperidin-4-yl, 1-, 3- or 4-homopiperidinyl, piperazin-1-yl,homopiperazin-1-yl, 1-, 2- or 3-pyrrolidinylmethyl, morpholinomethyl,piperidinomethyl, 3- or 4-piperidinylmethyl, 1-, 3- or4-homopiperidinylmethyl, 2-pyrrolidin-1-ylethyl,3-pyrrolidin-1-ylpropyl, 2-pyrrolidin-2-ylethyl,3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl,2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethyl,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propyl, 2-piperidinoethyl,3-piperidinopropyl, 2-piperidin-3-ylethyl, 2-piperidin-4-ylethyl,2-homopiperidin-1-ylethyl, 3-homopiperidin-1-ylpropyl,2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl, 2-homopiperazin-1-ylethylor 3-homopiperazin-1-ylpropyl,

[0221] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin the Q¹-Z— group are optionally separated by the insertion intothe chain of a group selected from O, NH, CONH, NHCO, CH═CH and C≡C,

[0222] and wherein any CH₂ or CH₃ group within the Q¹-Z— groupoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, methoxy, methylsulphonyl, methylamino anddimethylamino, or from a group of the formula:

—X⁷-Q⁸

[0223] wherein X⁷ is a direct bond or is selected from O, NH, CONH, NHCOand CH₂O and Q⁸ is pyridyl, pyridylmethyl, pyrrolidin-1-yl,pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidin-4-yl,piperazin-1-yl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl,pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl,2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl,3-piperidinopropyl, piperidin-3-ylmethyl, 2-piperidin-3-ylethyl,piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, 2-piperazin-1-ylethyl or3-piperazin-1-ylpropyl,

[0224] and wherein any aryl, heteroaryl or heterocyclyl group within theQ¹-Z— group optionally bears 1, 2 or 3 substituents, which may be thesame or different, selected from fluoro, chloro, trifluoromethyl,hydroxy, amino, carbamoyl, methyl, ethyl and methoxy, or optionallybears 1 substituent selected from a group of the formula:

—X⁸—R¹⁵

[0225] wherein X⁸ is a direct bond or is selected from O and NH and R ¹⁵is 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl,aminomethyl, 2-aminoethyl, 3-aminopropyl, methylaminomethyl,2-methylaminoethyl, 3-methylaminopropyl, 2-ethylaminoethyl,3-ethylaminopropyl, dimethylaminomethyl, 2-dimethylaminoethyl,3-dimethylaminopropyl, acetamidomethyl, methoxycarbonylaminomethyl,ethoxycarbonylaminomethyl or tert-butoxycarbonylaminomethyl, and from agroup of the formula:

—X⁹-Q⁹

[0226] wherein X⁹ is a direct bond or is selected from O and NH and Q⁹is pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl,3-pyrrolidin-1-ylpropyl, morpholinomethyl, 2-morpholinoethyl,3-morpholinopropyl, piperidinomethyl, 2-piperidinoethyl,3-piperidinopropyl, piperazin-1-ylmethyl, 2-piperazin-1-ylethyl or3-piperazin-1-ylpropyl, each of which optionally bears 1 or 2substituents, which may be the same or different, selected from fluoro,chloro, methyl and methoxy,

[0227] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo substituents;

[0228] (p) the Q¹-Z— group is selected from phenoxy, phenylthio,anilino, benzyloxy, cyclopropylmethoxy, tetrahydrofuran-3-yloxy, 3- or4-tetrahydropyranyloxy, 2-imidazol-1-ylethoxy, 3-imidazol-1-ylpropoxy,2-(1,2,3-triazol-1-yl)ethoxy, 2-(1,2,4-triazol-1-yl)ethoxy,3-(1,2,3-triazol-1-yl)propoxy, 3-(1,2,4-triazol-1-yl)propoxy,pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy,pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy,3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy,piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy,2-piperidin-4-ylethoxy, homopiperidin-3-yloxy, homopiperidin-4-yloxy,homopiperidin-3-ylmethoxy, 2-homopiperidin-1-ylethoxy,3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-homopiperazin-1-ylethoxy,3-homopiperazin-1-ylpropoxy, 2-pyrrolidin-1-ylethylamino,3-pyrrolidin-1-ylpropylamino, pyrrolidin-3-ylamino,pyrrolidin-2-ylmethylamino, 2-pyrrolidin-2-ylethylamino,3-pyrrolidin-2-ylpropylamino, 2-morpholinoethylamino,3-morpholinopropylamino,2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethylamino,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propylamino,2-piperidinoethylamino, 3-piperidinopropylamino, piperidin-3-ylamino,piperidin-4-ylamino, piperidin-3-ylmethylamino,2-piperidin-3-ylethylamino, piperidin-4-ylmethylamino,2-piperidin-4-ylethylamino, homopiperidin-3-ylamino,homopiperidin-4-ylamino, homopiperidin-3-ylmethylamino,2-homopiperidin-1-ylethylamino, 3-homopiperidin-1-ylpropylamino,2-piperazin-1-ylethylamino, 3-piperazin-1-ylpropylamino,2-homopiperazin-1-ylethylamino or 3-homopiperazin-1-ylpropylamino,

[0229] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin the Q¹-Z— group are optionally separated by the insertion intothe chain of a group selected from O, NH, CH═CH and C≡C,

[0230] and wherein any CH₂ or CH₃ group within the Q¹-Z— groupoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, methoxy, methylsulphonyl, methylamino anddimethylamino,

[0231] and wherein any phenyl or heterocyclyl group within the Q¹-Z—group optionally bears 1 or 2 substituents, which may be the same ordifferent, selected from fluoro, chloro, trifluoromethyl, hydroxy,amino, carbamoyl, methyl, ethyl and methoxy, and a piperidin-3-ylmethylor piperidin-4-ylmethyl group within the Q¹-Z— group is optionallyN-substituted with 2-methoxyethyl, 3-methoxypropyl, 2-aminoethyl,3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl,2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-pyrrolidin-1-ylethyl,3-pyrrolidin-1-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl,2-piperidinoethyl, 3-piperidinopropyl, 2-piperazin-1-ylethyl or3-piperazin-1-ylpropyl, the last 8 of which substituents each optionallybears 1 or 2 substituents, which may be the same or different, selectedfrom fluoro, chloro, methyl and methoxy,

[0232] and wherein any heterocyclyl group within the Q¹-Z groupoptionally bears 1 or 2 oxo substituents;

[0233] (q) the Q¹-Z— group is selected from phenoxy, benzyloxy,tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,tetrahydropyran-4-yloxy, 2-imidazol-1-ylethoxy,2-(1,2,4-triazol-1-yl)ethoxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy,piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy,2-piperidin-4-ylethoxy, 2-homopiperidin-1-ylethoxy,3-homopiperidin-1-ylpropoxy, homopiperidin-3-yloxy,homopiperidin-4-yloxy, homopiperidin-3-ylmethoxy,2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy,2-homopiperazin-1-ylethoxy or 3-homopiperazin-1-ylpropoxy,

[0234] and wherein any CH₂ or CH₃ group within the Q¹-Z— groupoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, methoxy, methylsulphonyl, methylamino anddimethylamino,

[0235] and wherein any phenyl or heterocyclyl group within the Q¹-Z—group optionally bears 1 or 2 substituents, which may be the same ordifferent, selected from fluoro, chloro, trifluoromethyl, hydroxy,amino, methyl, ethyl and methoxy,

[0236] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo substituents;

[0237] (r) Z is selected from O, S, SO, SO₂, N(R¹¹) and CO wherein R¹¹is hydrogen or (1-6C)alkyl, and Q¹ is (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,

[0238] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin the Q¹-Z— group are optionally separated by the insertion intothe chain of a group selected from O, N(R¹²), CON(R¹²), N(R¹²)CO, CH═CHand C≡C wherein R¹² is hydrogen or (1-6C)alkyl,

[0239] and wherein any CH₂ or CH₃ group within the Q¹-Z— groupoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylsulphonyl,(1-6C)alkylamino and di-[(1-6C)alkyl]amino, or from a group of theformula:

—X⁷-Q⁸

[0240] wherein X⁷ is a direct bond or is selected from O, N(R¹⁴),CON(R¹⁴), N(R¹⁴)CO and C(R¹⁴)₂O, wherein R¹⁴ is hydrogen or (1-6C)alkyl,and Q⁸ is heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl,

[0241] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1, 2 or 3 substituents, which may be the same ordifferent, selected from halogeno, trifluoromethyl, hydroxy, amino,carbamoyl, (1-6C)alkyl, (1-6C)alkoxy, N-(1-6C)alkylcarbamoyl andN,N-di-[(1-6C)alkyl]carbamoyl, or optionally bears 1 substituentselected from a group of the formula:

—X⁸—R¹⁵

[0242] wherein X⁴ is a direct bond or is selected from O and N(R¹⁶),wherein R¹⁶ is hydrogen or (1-6C)alkyl, and R¹⁵ is hydroxy-(1-6C)alkyl,(1-6C)alkoxy-(1-6C)alkyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl,(2-6C)alkanoylamino-(1-6C)alkyl or(1-6C)alkoxycarbonylamino-(1-6C)alkyl, and a group of the formula:

—X⁹-Q⁹

[0243] wherein X⁹ is a direct bond or is selected from O and N(R¹⁷),wherein R¹⁷ is hydrogen or (1-6C)alkyl, and Q⁹ is heterocyclyl orheterocyclyl-(1-6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from halogeno, (1-6C)alkyland (1-6C)alkoxy,

[0244] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo substituents;

[0245] (s) Z is selected from O, S, SO, SO₂ and NH and Q¹ isoxetan-3-yl, tetrahydrofuran-3-yl, 3- or 4-tetrahydropyranyl, 3- or4-oxepanyl, 1-, 2- or 3-pyrrolidinyl, morpholino,1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl, piperidino, piperidin-3-yl,piperidin-4-yl, 1-, 3- or 4-homopiperidinyl, piperazin-1-yl,homopiperazin-1-yl, 1-, 2- or 3-pyrrolidinylmethyl, morpholinomethyl,piperidinomethyl, 3- or 4-piperidinylmethyl, 1-, 3- or4-homopiperidinylmethyl, 2-pyrrolidin-1-ylethyl,3-pyrrolidin-1-ylpropyl, 2-pyrrolidin-2-ylethyl,3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl,2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethyl,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propyl, 2-piperidinoethyl,3-piperidinopropyl, 2-piperidin-3-ylethyl, 2-piperidin-4-ylethyl,2-homopiperidin-1-ylethyl, 3-homopiperidin-1-ylpropyl,2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl, 2-homopiperazin-1-ylethylor 3-homopiperazin-1-ylpropyl,

[0246] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin the Q¹-Z— group are optionally separated by the insertion intothe chain of a group selected from O, NH, CONH, NHCO, CH═CH and C≡C,

[0247] and wherein any CH₂ or CH₃ group within the Q¹-Z— groupoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, methoxy, methylsulphonyl, methylamino anddimethylamino, or from a group of the formula:

—X⁷-Q⁸

[0248] wherein X⁷ is a direct bond or is selected from O, NH, CONH, NHCOand CH₂O and Q⁸ is pyridyl, pyridylmethyl, pyrrolidin-1-yl,pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidin-4-yl,piperazin-1-yl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl,pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl,2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl,3-piperidinopropyl, piperidin-3-ylmethyl, 2-piperidin-3-ylethyl,piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, 2-piperazin-1-ylethyl or3-piperazin-1-ylpropyl,

[0249] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1, 2 or 3 substituents, which may be the same ordifferent, selected from fluoro, chloro, trifluoromethyl, hydroxy,amino, carbamoyl, methyl, ethyl and methoxy, or optionally bears 1substituent selected from a group of the formula:

—X⁸—R¹⁵

[0250] wherein X8 is a direct bond or is selected from O and NH and R¹⁵is 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl,aminomethyl, 2-aminoethyl, 3-aminopropyl, methylaminomethyl,2-methylaminoethyl, 3-methylaminopropyl, 2-ethylaminoethyl,3-ethylaminopropyl, dimethylaminomethyl, 2-dimethylaminoethyl,3-dimethylaminopropyl, acetamidomethyl, methoxycarbonylaminomethyl,ethoxycarbonylaminomethyl or tert-butoxycarbonylaminomethyl, and from agroup of the formula:

—X⁹-Q⁹

[0251] wherein X⁹ is a direct bond or is selected from O and NH and Q⁹is pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl,3-pyrrolidin-1-ylpropyl, morpholinomethyl, 2-morpholinoethyl,3-morpholinopropyl, piperidinomethyl, 2-piperidinoethyl,3-piperidinopropyl, piperazin-1-ylmethyl, 2-piperazin-1-ylethyl or3-piperazin-1-ylpropyl, each of which optionally bears 1 or 2substituents, which may be the same or different, selected from fluoro,chloro, methyl and methoxy,

[0252] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo substituents;

[0253] (t) the Q¹-Z— group is selected from cyclopropylmethoxy,tetrahydrofuran-3-yloxy, 3- or 4-tetrahydropyranyloxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy,pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy,3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy,piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy,2-piperidin-4-ylethoxy, homopiperidin-3-yloxy, homopiperidin-4-yloxy,homopiperidin-3-ylmethoxy, 2-homopiperidin-1-ylethoxy,3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-homopiperazin-1-ylethoxy,3-homopiperazin-1-ylpropoxy, 2-pyrrolidin-1-ylethylamino,3-pyrrolidin-1-ylpropylamino, pyrrolidin-3-ylamino,pyrrolidin-2-ylmethylamino, 2-pyrrolidin-2-ylethylamino,3-pyrrolidin-2-ylpropylamino, 2-morpholinoethylamino,3-morpholinopropylamino,2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethylamino,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propylamino,2-piperidinoethylamino, 3-piperidinopropylamino, piperidin-3-ylamino,piperidin-4-ylamino, piperidin-3-ylmethylamino,2-piperidin-3-ylethylamino, piperidin-4-ylmethylamino,2-piperidin-4-ylethylamino, homopiperidin-3-ylamino,homopiperidin-4-ylamino, homopiperidin-3-ylmethylamino,2-homopiperidin-1-ylethylamino, 3-homopiperidin-1-ylpropylamino,2-piperazin-1-ylethylamino, 3-piperazin-1-ylpropylamino,2-homopiperazin-1-ylethylamino or 3-homopiperazin-1-ylpropylamino,

[0254] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin the Q¹-Z— group are optionally separated by the insertion intothe chain of a group selected from O, NH, CH═CH and C≡C,

[0255] and wherein any CH₂ or CH₃ group within the Q¹-Z— groupoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, methoxy, methylsulphonyl, methylamino anddimethylamino,

[0256] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 substituents, which may be the same ordifferent, selected from fluoro, chloro, trifluoromethyl, hydroxy,amino, carbamoyl, methyl, ethyl and methoxy, and a piperidin-3-ylmethylor piperidin-4-ylmethyl group within the Q¹-Z group is optionallyN-substituted with 2-methoxyethyl, 3-methoxypropyl, 2-aminoethyl,3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl,2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-pyrrolidin-1-ylethyl,3-pyrrolidin-1-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl,2-piperidinoethyl, 3-piperidinopropyl, 2-piperazin-1-ylethyl or3-piperazin-1-ylpropyl, the last 8 of which substituents each optionallybears 1 or 2 substituents, which may be the same or different, selectedfrom fluoro, chloro, methyl and methoxy,

[0257] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo substituents;

[0258] (u) the Q¹-Z— group is selected from tetrahydrofuran-3-yloxy,tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy,pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy,3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy,piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy,2-piperidin-4-ylethoxy, 2-homopiperidin-1-ylethoxy,3-homopiperidin-1-ylpropoxy, homopiperidin-3-yloxy,homopiperidin-4-yloxy, homopiperidin-3-ylmethoxy,2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy,2-homopiperazin-1-ylethoxy or 3-homopiperazin-1-ylpropoxy,

[0259] and wherein any CH₂ or CH₃ group within the Q¹-Z— groupoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, methoxy, methylsulphonyl, methylamino anddimethylamino,

[0260] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 substituents, which may be the same ordifferent, selected from fluoro, chloro, trifluoromethyl, hydroxy,amino, methyl, ethyl and methoxy,

[0261] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo substituents;

[0262] (v) Q² is an aryl group of formula Ia

[0263] wherein G₁ is selected from halogeno, trifluoromethyl, cyano,hydroxy, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (1-6C)alkoxy,

[0264] and each of G², G³, G⁴ and G⁵, which may be the same ordifferent, is selected from hydrogen, halogeno, trifluoromethyl, cyano,hydroxy, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (1-6C)alkoxy;

[0265] (w) Q² is an aryl group of formula Ia wherein G¹ and G² togetherform a group of formula: —CH═CH—CH═CH—, —N═CH—CH═CH—, —CH═N—CH═CH—,—CH═CH—N═CH—, —CH═CH—CH═N—, —CH═CH—O—, —O—CH═CH—, —CH═CH—S—, —S—CH═CH—,—O—CH₂—O— or —O—CH₂—CH₂—O—, and the 9- or 10-membered bicyclicheteroaryl or heterocyclic ring formed when G¹ and G² together arelinked optionally bears on the heteroaryl or heterocyclic portion of thebicyclic ring 1, 2 or 3 substituents, which may be the same ordifferent, selected from halogeno, trifluoromethyl, cyano, hydroxy,(1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (1-6C)alkoxy, and anybicyclic heterocyclic ring so formed optionally bears 1 or 2 oxo orthioxo groups,

[0266] and each of G³, G⁴ and G which may be the same or different, isselected from hydrogen, halogeno, trifluoromethyl, cyano, hydroxy,(1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (1-6C)alkoxy;

[0267] (x) Q² is an aryl group of formula Ia wherein G¹ is selected fromhalogeno, trifluoromethyl, cyano, hydroxy, (1-6C)alkyl, (2-8C)alkenyl,(2-8C)alkynyl and (1-6C)alkoxy,

[0268] and G² and G³ together or G³ and G⁴ together form a group offormula —CH═CH—CH═CH—, —N═CH—CH═CH—, —CH═N—CH═CH—, —CH═CH—N═CH—,—CH═CH—CH—N—, —CH═CH—O—, —O—CH═CH—, —CH═CH—S—,—S—CH═CH—, —O—CH₂—O— or—O—CH₂—CH₂—O—,

[0269] and the 9- or 10-membered bicyclic heteroaryl or heterocyclicring formed when G² and G³ together or G³ and G⁴ together are linkedoptionally bears on the heteroaryl or heterocyclic portion of thebicyclic ring 1, 2 or 3 substituents, which may be the same ordifferent, selected from halogeno, trifluoromethyl, cyano, hydroxy,(1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (1-6C)alkoxy, and anybicyclic heterocyclic ring so formed optionally bears 1 or 2 oxo orthioxo groups,

[0270] and each of G⁴ and G⁵ or G² and G⁵ as appropriate, which may bethe same or different, is selected from hydrogen, halogeno,trifluoromethyl, cyano, hydroxy, (1-6C)alkyl, (2-8C)alkenyl,(2-8C)alkynyl and (1-6C)alkoxy;

[0271] (y) Q² is an aryl group of formula Ia wherein G¹ is selected fromfluoro, chloro, bromo, iodo, trifluoromethyl, cyano, hydroxy, methyl,ethyl, vinyl, allyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl,methoxy and ethoxy,

[0272] and each of G², G³, G⁴ and G⁵, which may be the same ordifferent, is selected from hydrogen, fluoro, chloro, bromo,trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl,isopropenyl, ethynyl, 1-propynyl, 2-propynyl, methoxy and ethoxy;

[0273] (z) Q² is an aryl group of formula Ia wherein G¹ is selected fromfluoro, chloro, bromo, iodo, trifluoromethyl, cyano, methyl, ethyl,vinyl, allyl, isopropenyl, ethynyl, methoxy and ethoxy,

[0274] and each of G², G³, G⁴ and G⁵, which may be the same ordifferent, is selected from hydrogen, fluoro, chloro, bromo,trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl,isopropenyl, ethynyl, methoxy and ethoxy;

[0275] (aa) Q² is an aryl group of formula Ia wherein G¹ and G² togetherform a group of formula: —CH═CH—CH═CH—, —O—CH═CH— or —O—CH₂—O—,

[0276] and the 9- or 10-membered bicyclic heteroaryl or heterocyclicring so formed optionally bears on the heteroaryl or heterocyclicportion of the bicyclic ring 1 or 2 substituents, which may be the sameor different, selected from fluoro, chloro, bromo, trifluoromethyl,cyano, hydroxy, methyl, ethyl, methoxy and ethoxy, and any bicyclicheterocyclic ring so formed optionally bears 1 or 2 oxo or thioxogroups,

[0277] and each of G³, G⁴ and G⁵, which may be the same or different, isselected from hydrogen, fluoro, chloro, bromo, trifluoromethyl, cyano,hydroxy, methyl, ethyl, methoxy and ethoxy;

[0278] (bb) Q² is an aryl group of formula Ia wherein G¹ is selectedfrom fluoro, chloro, bromo, iodo, trifluoromethyl, cyano, methyl, ethyl,methoxy and ethoxy,

[0279] and G² and G³ together or G³ and G⁴ together form a group offormula —CH═CH—CH═CH—, —O—CH═CH— or —O—CH₂—O—,

[0280] and the 9- or 10-membered bicyclic heteroaryl or heterocyclicring so formed optionally bears on the heteroaryl or heterocyclicportion of the bicyclic ring 1 or 2 substituents, which may be the sameor different, selected from fluoro, chloro, bromo, trifluoromethyl,cyano, hydroxy, methyl, ethyl, methoxy and ethoxy, and any bicyclicheterocyclic ring so formed optionally bears 1 or 2 oxo or thioxogroups,

[0281] and each of G⁴ and G⁵ or G² and G⁵ as appropriate, which may bethe same or different, is selected from hydrogen, fluoro, chloro, bromo,trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy;

[0282] (cc) Q² is an aryl group of formula Ia wherein G¹ and G² togetherform a group of formula: —O—CH₂—O—,

[0283] and the 9-membered bicyclic heterocyclic ring so formedoptionally bears on the heterocyclic portion of the bicyclic ring 1 or 2substituents, which may be the same or different, selected from fluoro,chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxyand ethoxy, and the bicyclic heterocyclic ring so formed optionallybears 1 oxo or thioxo groups,

[0284] each of G³ and G⁴, which may be the same or different, isselected from hydrogen, fluoro, chloro, bromo, trifluoromethyl, cyano,hydroxy, methyl, ethyl, methoxy and ethoxy, and G⁵ is selected fromhydrogen, fluoro, chloro or bromo;

[0285] (dd) m is 1 or 2, and each R¹ group, which may be the same ordifferent, is selected from halogeno, trifluoromethyl, hydroxy, amino,carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoylamino,N-(1-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino,N-(1-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino andN-(1-6C)alkyl-(3-6C)alkynoylamino, or from a group of the formula:

Q³-X¹—

[0286] wherein X¹ is a direct bond or is selected from O, N(R⁴),CON(R⁴), N(R⁴)CO and OC(R⁴)₂ wherein R⁴ is hydrogen or (1-6C)alkyl, andQ³ is aryl, aryl-(1-6C)alkyl, cycloalkyl-(1-6C)alkyl, heteroaryl,heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,

[0287] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin a R¹ substituent are optionally separated by the insertion intothe chain of a group selected from O, N(R⁵), CON(R⁵), N(R⁵)CO, CH═CH andC≡C wherein R⁵ is hydrogen or (1-6C)alkyl,

[0288] and wherein any CH₂═CH— or HC≡C— group within a R¹ substituentoptionally bears at the terminal CH₂ ₂═ or HC≡ position a substituentselected from carbamoyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl orfrom a group of the formula:

Q⁴-X²—

[0289] wherein X² is a direct bond or is CO or N(R⁶)CO, wherein R⁶ ishydrogen or (1-6C)alkyl, and Q⁴ is heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl,

[0290] and wherein any CH₂ or CH₃ group within a R¹ substituentoptionally bears on each said CH₂ or CH₃ group a,substituent selectedfrom hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylsulphonyl,(1-6C)alkylamino and di-[(1-6C)alkyl]amino, or from a group of theformula:

—X³-Q⁵

[0291] wherein X³ is a direct bond or is selected from O, N(R⁷),CON(R⁷), N(R⁷)CO and C(R⁷)₂O, wherein R⁷ is hydrogen or (1-6C)alkyl, andQ⁵ is heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl,

[0292] and wherein any aryl, heteroaryl or heterocyclyl group within asubstituent on R¹ optionally bears 1, 2 or 3 substituents, which may bethe same or different, selected from halogeno, trifluoromethyl, hydroxy,amino, carbamoyl, (1-6C)alkyl, (1-6C)alkoxy, N-(1-6C)alkylcarbamoyl andN,N-di-[(1-6C)alkyl]carbamoyl, or optionally bears 1 substituentselected from a group of the formula:

—X⁴—R⁸

[0293] wherein X⁴ is a direct bond or is selected from O and N(R⁹),wherein R⁹ is hydrogen or (1-6C)alkyl, and R⁸ is hydroxy-(1-6C)alkyl,(1-6C)alkoxy-(1-6C)alkyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl,(2-6C)alkanoylamino-(1-6C)alkyl or(1-6C)alkoxycarbonylamino-(1-6C)alkyl, and from a group of the formula:

—X⁵-Q⁶

[0294] wherein X⁵ is a direct bond or is selected from O, CO and N(R¹⁰),wherein R¹⁰ is hydrogen or (1-6C)alkyl, and Q⁶ is heterocyclyl orheterocyclyl-(1-6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from halogeno, (1-6C)alkyland (1-6C)alkoxy,

[0295] and wherein any heterocyclyl group within a substituent on R¹optionally bears 1 or 2 oxo substituents; and

[0296] (ee) the Q¹-Z— group is selected from (1-6C)alkyl, (2-8C)alkenyl,(2-8C)alkynyl, (1-6C)alkoxy, (2-8C)alkenyloxy, (2-8C)alkynyloxy,halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl,cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, halogeno-(1-6C)alkoxy,hydroxy-(1-6C)alkoxy, (1-6C)alkoxy-(1-6C)alkoxy, cyano-(1-6C)alkoxy,amino-(1-6C)alkoxy, (1-6C)alkylamino-(1-6C)alkoxy anddi-[(1-6C)alkyl]amino-(1-6C)alkoxy,

[0297] or Z is a direct bond or is selected from O, S, SO, SO₂, N(R¹¹)and CO wherein R¹¹ is hydrogen or (1-6C)alkyl, and Q¹ is aryl,aryl-(1-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl,heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl,

[0298] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin the Q¹-Z— group are optionally separated by the insertion intothe chain of a group selected from O, N(R¹²), CON(R¹²), N(R¹²)CO, CH═CHand C≡C wherein R¹² is hydrogen or (1-6C)alkyl,

[0299] and wherein any CH₂═CH— or HC≡C— group within the Q¹-Z— groupoptionally bears at the terminal CH₂═ or HC≡ position a substituentselected from carbamoyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl orfrom a group of the formula:

Q⁷-X⁶—

[0300] wherein X⁶ is a direct bond or is CO or N(R¹³)CO, wherein R¹³ ishydrogen or (1-6C)alkyl, and Q⁷ is heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl,

[0301] and wherein any CH₂ or CH₃ group within the Q¹-Z— groupoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylsulphonyl,(1-6C)alkylamino and di-[(1-6C)alkyl]amino, or from a group of theformula:

—X⁸—R¹⁵

[0302] wherein X⁷ is a direct bond or is selected from O, N(R¹R⁴),CON(R¹⁴), N(R¹⁴)CO and C(R¹⁴)₂O, wherein R¹⁴ is hydrogen or (1-6C)alkyl,and Q⁸ is heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl,

[0303] and wherein any aryl, heteroaryl or heterocyclyl group within theQ¹-Z— group optionally bears 1, 2 or 3 substituents, which may be thesame or different, selected from halogeno, trifluoromethyl, hydroxy,amino, carbamoyl, (1-6C)alkyl, (1-6C)alkoxy, N-(1-6C)alkylcarbamoyl andN,N-di-[(1-6C)alkyl]carbamoyl, or optionally bears 1 substituentselected from a group of the formula:

—X⁸—R¹⁵

[0304] wherein X⁴ is a direct bond or is selected from O and N(R¹⁶),wherein R¹⁶ is hydrogen or (1-6C)alkyl, and R¹⁵ is hydroxy-(1-6C)alkyl,(1-6C)alkoxy-(1-6C)alkyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl,(2-6C)alkanoylamino-(1-6C)alkyl or(1-6C)alkoxycarbonylamino-(1-6C)alkyl, and a group of the formula:

—X⁹-Q⁹

[0305] wherein X⁹ is a direct bond or is selected from O, CO and N(R¹⁷),wherein R¹⁷ is hydrogen or (1-6C)alkyl, and Q⁹ is heterocyclyl orheterocyclyl-(1-6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from halogeno, (1-6C)alkyland (1-6C)alkoxy,

[0306] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo substituents.

[0307] As stated hereinbefore, certain compounds of the presentinvention, possess substantially better potency against the Src familyof non-receptor tyrosine kinases, for example c-Src and/or c-Yes, thanagainst EGF receptor tyrosine kinase or VEGF receptor tyrosine kinase.Particular groups of novel compounds of the invention that possess suchselectivity include, for example, quinazoline derivatives of the FormulaI, or pharmaceutically-acceptable salts thereof, wherein each of m, R¹,R², R³, Z and Q¹ has any of the meanings defined hereinbefore and:

[0308] (a) Q² is an aryl group of formula Ia

[0309] wherein G¹ is halogeno or trifluoromethyl,

[0310] each of G² and G⁵ is hydrogen,

[0311] G³ is selected from hydrogen, halogeno, trifluoromethyl, cyano,hydroxy, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (1-6C)alkoxy,

[0312] and G⁴ is halogeno or (1-6C)alkoxy;

[0313] (b) Q² is an aryl group of formula Ia wherein G¹ is fluoro,chloro, bromo, iodo or trifluoromethyl,

[0314] each of G² and G⁵ is hydrogen,

[0315] G³ is selected from hydrogen, fluoro, chloro, bromo,trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl,isopropenyl, ethynyl, methoxy and ethoxy, and G⁴ is fluoro, chloro,bromo, methoxy or ethoxy;

[0316] (c) Q² is an aryl group of formula la wherein G¹ and G² togetherform a group of formula: —O—CH₂—O—,

[0317] each of G³ and G⁴, which may be the same or different, isselected from hydrogen, halogeno, trifluoromethyl, cyano, hydroxy,(1-6C)alkyl and (1-6C)alkoxy, and G is halogeno; or

[0318] (d) Q² is an aryl group of formula Ia wherein G¹ and G² togetherform a group of formula: —O—CH₂—O—,

[0319] each of G³ and G⁴, which may be the same or different, isselected from hydrogen, fluoro, chloro, bromo, trifluoromethyl, cyano,hydroxy, methyl, ethyl, methoxy and ethoxy,

[0320] and G⁵ is selected from fluoro, chloro or bromo.

[0321] A preferred compound of the invention is a quinazoline derivativeof the Formula I wherein:

[0322] m is 0 or m is 1 and the R¹ group is located at the 6- or7-position and is selected from hydroxy, amino, methyl, ethyl, propyl,methoxy, ethoxy, propoxy, methylamino, ethylamino, dimethylamino,diethylamino, acetamido, propionamido, benzyloxy, 2-imidazol-1-ylethoxy,2-(1,2,4-triazol-1-yl)ethoxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy,piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy,2-piperidin-4-ylethoxy, 2-homopiperidin-1-ylethoxy,3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-homopiperazin-1-ylethoxy and3-homopiperazin-1-ylpropoxy,

[0323] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin a R¹ substituent are optionally separated by the insertion intothe chain of a group selected from O, NH, CH═CH and C≡C,

[0324] and wherein any CH₂ or CH₃ group within a R¹ substituentoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, methoxy, methylsulphonyl, methylamino anddimethylamino,

[0325] and wherein any phenyl or heterocyclyl group within a substituenton R¹ optionally bears 1 or 2 substituents, which may be the same ordifferent, selected from fluoro, chloro, trifluoromethyl, hydroxy,amino, methyl, ethyl and methoxy,

[0326] and wherein any heterocyclyl group within a substituent on R¹optionally bears 1 or 2 oxo substituents;

[0327] the Q¹-Z— group is selected from propoxy, isopropoxy,2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 3-methoxypropoxy,cyclopentyloxy, cyclohexyloxy, phenoxy, benzyloxy,tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,tetrahydropyran-4-yloxy, 2-imidazol-1-ylethoxy,2-(1,2,4-triazol-1-yl)ethoxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1 ,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy,piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy,2-piperidin-4-ylethoxy, 2-homopiperidin-1-ylethoxy,3-homopiperidin-1-ylpropoxy, homopiperidin-3-yloxy,homopiperidin-4-yloxy, homopiperidin-3-ylmethoxy,2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy,2-homopiperazin-1-ylethoxy or 3-homopiperazin-1-ylpropoxy,

[0328] and wherein any CH₂ or CH₃ group within the Q¹-Z— groupoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, methoxy, methylsulphonyl, methylamino anddimethylamino,

[0329] and wherein any phenyl or heterocyclyl group within the Q¹-Z—group optionally bears 1 or 2 substituents, which may be the same ordifferent, selected from fluoro, chloro, trifluoromethyl, hydroxy,amino, methyl, ethyl and methoxy,

[0330] and wherein any heterocyclyl- group within the Q¹-Z— groupoptionally bears 1 or 2 oxo substituents;

[0331] each of R² and R³ is hydrogen; and

[0332] Q² is an aryl group of formula Ia

[0333] wherein G¹ is selected from fluoro, chloro, bromo, iodo,trifluoromethyl, cyano, methyl, ethyl, vinyl, allyl, isopropenyl,ethynyl, methoxy and ethoxy, and each of G², G³, G⁴ and G⁵, which may bethe same or different, is selected from hydrogen, fluoro, chloro, bromo,trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl,isopropenyl, ethynyl, methoxy and ethoxy,

[0334] or G¹ and G² together form a group of formula: —CH═CH—CH═CH—,—O—CH═CH— or —O—CH₂—O—, and the 9- or 10-membered bicyclic heteroaryl orheterocyclic ring so formed optionally bears on the heteroaryl orheterocyclic portion of the bicyclic ring 1 or 2 substituents, which maybe the same or different, selected from fluoro, chloro, bromo,trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy, andany bicyclic heterocyclic ring so formed optionally bears 1 or 2 oxo orthioxo groups, and each of G³, G⁴ and G⁵, which may be the same ordifferent, is selected from hydrogen, fluoro, chloro, bromo,trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy; or apharmaceutically-acceptable acid-addition salt thereof.

[0335] A further preferred compound of the invention is a quinazolinederivative of the Formula I wherein:

[0336] m is 1 and the R¹ group is located at the 7-position and isselected from hydroxy, methoxy, ethoxy, propoxy, benzyloxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 2-hydroxyethoxy, 3-hydroxypropoxy,2-methoxyethoxy, 3-methoxypropoxy, 2-methylsulphonylethoxy,3-methylsulphonylpropoxy and 2-(2-methoxyethoxy)ethoxy;

[0337] and wherein any CH₂ group within a R¹ substituent that isattached to two carbon atoms optionally bears a hydroxy group on saidCH₂ group;

[0338] the Q¹-Z— group is selected from propoxy, isopropoxy,2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 3-methoxypropoxy,cyclopentyloxy, cyclohexyloxy, tetrahydrofuran-3-yloxy,tetrahydropyran-4-yloxy, 2-imidazol-1-ylethoxy,2-(1,2,4-triazol-1-yl)ethoxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy,N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-yloxy, N-methylpiperidin-3-yloxy,piperidin-4-yloxy, N-methylpiperidin-4-yloxy, piperidin-3-ylmethoxy,N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy,N-methylpiperidin-4-ylmethoxy, 2-(4-methylpiperazin-1-yl)ethoxy and3-(4-methylpiperazin-1-yl)propoxy,

[0339] and wherein any CH₂ group within the Q¹-Z— group that is attachedto two carbon atoms optionally bears a hydroxy group on said CH₂ group;

[0340] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo substituents;

[0341] each of l² and R³ is hydrogen; and

[0342] Q² is an aryl group of formula Ia

[0343] wherein G¹ is selected from fluoro, chloro, bromo, iodo,trifluoromethyl, cyano, methyl, ethyl, vinyl, isopropenyl and ethynyl,each of G³ and G⁴, which may be the same or different, is selected fromhydrogen, fluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy,methyl, ethyl, vinyl, allyl, isopropenyl, ethynyl, methoxy and ethoxy,and each of G² and G⁵ is hydrogen, or G¹ and G² together form a group offormula: —CH═CH—CH═CH—, —O—CH═CH— or —O—CH₂—O—, and the 9- or10-membered bicyclic heteroaryl or heterocyclic ring so formedoptionally bears on the heteroaryl or heterocyclic portion of thebicyclic ring 1 or 2 substituents, which may be the same or different,selected from fluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy,methyl and methoxy, and each of G³, G⁴ and G⁵, which may be the same ordifferent, is selected from hydrogen, fluoro, chloro, bromo,trifluoromethyl, cyano, hydroxy, methyl and methoxy;

[0344] or a pharmaceutically-acceptable acid-addition salt thereof.

[0345] A further preferred compound of the invention is a quinazolinederivative of the Formula I wherein:

[0346] m is 1 and the R¹ group is located at the 7-position and isselected from hydroxy, methoxy, benzyloxy, 3-morpholinopropoxy,2-hydroxy-3-morpholinopropoxy, 3-(4-methylpiperazin-1-yl)propoxy,2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy, 2-methoxyethoxy and2-(2-methoxyethoxy)ethoxy;

[0347] the Q¹-Z— group is selected from isopropoxy, 2-methoxyethoxy,cyclohexyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy,2-imidazol-1-ylethoxy, 2-(1,2,4-triazol-1-yl)ethoxy,3-pyrrolidin-1-ylpropoxy, N-methylpyrrolidin-3-yloxy,3-morpholinopropoxy, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy,2-piperidinoethoxy, N-methylpiperidin-4-yloxy, piperidin-4-ylmethoxy,N-methylpiperidin-4-ylmethoxy and 3-(4-methylpiperazin-1-yl)propoxy,

[0348] each of R² and R³ is hydrogen; and

[0349] Q² is an aryl group of formula Ia

[0350] wherein G¹ is selected from fluoro, chloro, bromo and iodo, eachof G³ and G⁴, which may be the same or different, is selected fromhydrogen, chloro and methoxy, and each of G² and G⁵ is hydrogen,

[0351] or G¹ and G² together form a group of formula: —CH═CH—CH═C(Cl)—,—O—CH═C(Cl)— or —O—CH₂—O—, and each of G³, G⁴ and G⁵ is hydrogen;

[0352] or a pharmaceutically-acceptable acid-addition salt thereof

[0353] A further preferred compound of the invention is a quinazolinederivative of the Formula I wherein:

[0354] m is 0 or m is 1 and the R¹ group is located at the 6- or7-position and is selected from hydroxy, amino, methyl, ethyl, propyl,methoxy, ethoxy, propoxy, methylamino, ethylamino, dimethylamino,diethylamino, acetamido, propionamido, benzyloxy, 2-imidazol-1-ylethoxy,2-(1,2,4-triazol-1-yl)ethoxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy,piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy,2-piperidin-4-ylethoxy, 2-homopiperidin-1-ylethoxy,3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-homopiperazin-1-ylethoxy and3-homopiperazin-1-ylpropoxy,

[0355] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin a R¹ substituent are optionally separated by the insertion intothe chain of a group selected from O, NH, CH═CH and C≡C,

[0356] and wherein any CH₂ or CH₃ group within a R¹ substituentoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, methoxy, methylsulphonyl, methylamino anddimethylamino,

[0357] and wherein any phenyl or heterocyclyl group within a substituenton R¹ optionally bears 1 or 2 substituents, which may be the same ordifferent, selected from fluoro, chloro, trifluoromethyl, hydroxy,amino, methyl, ethyl and methoxy,

[0358] and wherein any heterocyclyl group within a substituent on R¹optionally bears 1 or 2 oxo substituents;

[0359] the Q¹-Z— group is selected from phenoxy, benzyloxy,tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,tetrahydropyran-4-yloxy, 2-imidazol-1-ylethoxy,2-(1,2,4-triazol-1-yl)ethoxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy,piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy,2-piperidin-4-ylethoxy, 2-homopiperidin-1-ylethoxy,3-homopiperidin-1-ylpropoxy, homopiperidin-3-yloxy,homopiperidin-4-yloxy, homopiperidin-3-ylmethoxy,2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy,2-homopiperazin-1-ylethoxy or 3-homopiperazin-1-ylpropoxy,

[0360] and wherein any CH₂ or CH₃ group within the Q¹-Z— groupoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, methoxy, methylsulphonyl, methylamino anddimethylamino,

[0361] and wherein any phenyl or heterocyclyl group within the Q¹-Z—group optionally bears 1 or 2 substituents, which may be the same ordifferent, selected from fluoro, chloro, trifluoromethyl, hydroxy,amino, methyl, ethyl and methoxy,

[0362] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo substituents;

[0363] each of R² and R³ is hydrogen; and

[0364] Q² is an aryl group of formula Ia

[0365] wherein G¹ is selected from fluoro, chloro, bromo, iodo,trifluoromethyl, cyano, methyl, ethyl, vinyl, allyl, isopropenyl,ethynyl, methoxy and ethoxy, and each of G², G³, G⁴ and G⁵, which may bethe same or different, is selected from hydrogen, fluoro, chloro, bromo,trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl,isopropenyl, ethynyl, methoxy and ethoxy,

[0366] or G¹ and G² together form a group of formula: —CH═CH—CH═CH—,—O—CH═CH— or —O—CH₂—O—, and the 9- or 10-membered bicyclic heteroaryl orheterocyclic ring so formed optionally bears on the heteroaryl orheterocyclic portion of the bicyclic ring 1 or 2 substituents, which maybe the same or different, selected from fluoro, chloro, bromo,trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy, andany bicyclic heterocyclic ring so formed optionally bears 1 or 2 oxo orthioxo groups, and each of G³, G⁴ and G⁵, which may be the same ordifferent, is selected from hydrogen, fluoro, chloro, bromo,trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy;

[0367] or a pharmaceutically-acceptable acid-addition salt thereof.

[0368] A further preferred compound of the invention is a quinazolinederivative of the Formula I wherein:

[0369] m is 1 and the R¹ group is located at the 7-position and isselected from hydroxy, methoxy, ethoxy, propoxy, benzyloxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 2-hydroxyethoxy, 3-hydroxypropoxy,2-methoxyethoxy, 3-methoxypropoxy, 2-methylsulphonylethoxy,3-methylsulphonylpropoxy and 2-(2-methoxyethoxy)ethoxy;

[0370] and wherein any CH₂ group within a R¹ substituent that isattached to two carbon atoms optionally bears a hydroxy group on saidCH₂ group;

[0371] the Q¹-Z— group is selected from tetrahydrofuran-3-yloxy,tetrahydropyran-4-yloxy, 2-imidazol-1-ylethoxy,2-(1,2,4-triazol-1-yl)ethoxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy,N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-yloxy, N-methylpiperidin-3-yloxy,piperidin-4-yloxy, N-methylpiperidin-4-yloxy, piperidin-3-ylmethoxy,N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy,N-methylpiperidin-4-ylmethoxy, 2-(4-methylpiperazin-1-yl)ethoxy and3-(4-methylpiperazin-1-yl)propoxy,

[0372] and wherein any CH₂ group within the Q¹-Z— group that is attachedto two carbon atoms optionally bears a hydroxy group on said CH₂ group;

[0373] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo substituents;

[0374] each of R² and R³ is hydrogen; and

[0375] Q² is an aryl group of formula Ia

[0376] wherein G¹ is selected from fluoro, chloro, bromo, iodo,trifluoromethyl, cyano, methyl, ethyl, vinyl, isopropenyl and ethynyl,each of G³ and G⁴, which may be the same or different, is selected fromhydrogen, fluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy,methyl, ethyl, vinyl, allyl, isopropenyl, ethynyl, methoxy and ethoxy,and each of G² and G⁵ is hydrogen, or G¹ and G² together form a group offormula: —CH═CH—CH═CH—, —O—CH═CH— or —O—CH₂—O—, and the 9- or10-membered bicyclic heteroaryl or heterocyclic ring so formedoptionally bears on the heteroaryl or heterocyclic portion of thebicyclic ring 1 or 2 substituents, which may be the same or different,selected from fluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy,methyl and methoxy, and each of G³, G⁴ and G⁵, which may be the same ordifferent, is selected from hydrogen, fluoro, chloro, bromo,trifluoromethyl, cyano, hydroxy, methyl and methoxy;

[0377] or a pharmaceutically-acceptable acid-addition salt thereof.

[0378] A further preferred compound of the invention is a quinazolinederivative of the Formula I wherein:

[0379] m is 1 and the R¹ group is located at the 7-position and isselected from hydroxy, methoxy, benzyloxy, 3-morpholinopropoxy,2-hydroxy-3-morpholinopropoxy, 3-(4-methylpiperazin-1-yl)propoxy,2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy, 2-methoxyethoxy and2-(2-methoxyethoxy)ethoxy;

[0380] the Q¹-Z— group is selected from tetrahydrofuran-3-yloxy,tetrahydropyran-4-yloxy, 2-imidazol-1-ylethoxy,2-(1,2,4-triazol-1-yl)ethoxy, 3-pyrrolidin-1-ylpropoxy,N-methylpyrrolidin-3-yloxy, 3-morpholinopropoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,N-methylpiperidin-4-yloxy, piperidin-4-ylmethoxy,N-methylpiperidin-4-ylmethoxy and 3-(4-methylpiperazin-1-yl)propoxy,

[0381] each of R² and R³ is hydrogen; and

[0382] Q² is an aryl group of formula Ia

[0383] wherein G¹ is selected from fluoro, chloro, bromo and iodo, eachof G³ and G⁴, which may be the same or different, is selected fromhydrogen, chloro and methoxy, and each of G² and G⁵ is hydrogen,

[0384] or G¹ and G² together form a group of formula: —CH═CH—CH═C(Cl)—,—O—CH═C(Cl)— or —O—CH₂—O—, and each of G³, G⁴ and G⁵ is hydrogen;

[0385] or a pharmaceutically-acceptable acid-addition salt thereof.

[0386] A further preferred compound of the invention is a quinazolinederivative of the Formula I wherein:

[0387] m is 0 or m is 1 and the R¹ group is located at the 6- or7-position and is selected from hydroxy, amino, methyl, ethyl, propyl,methoxy, ethoxy, propoxy, methylamino, ethylamino, dimethylamino,diethylamino, acetamido, propionamido, benzyloxy, 2-imidazol-1-ylethoxy,2-(1,2,4-triazol-1-yl)ethoxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy,piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy,2-piperidin-4-ylethoxy, 2-homopiperidin-1-ylethoxy,3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-homopiperazin-1-ylethoxy and3-homopiperazin-1-ylpropoxy,

[0388] and wherein adjacent carbon atoms in any (2-6C)alkylene chainwithin a R¹ substituent are optionally separated by the insertion intothe chain of a group selected from O, NH, CH═CH and C≡C,

[0389] and wherein any CH₂ or CH₃ group within a R¹ substituentoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, methoxy, methylsulphonyl, methylamino anddimethylamino,

[0390] and wherein any phenyl or heterocyclyl group within a substituenton R¹ optionally bears 1 or 2 substituents, which may be the same ordifferent, selected from fluoro, chloro, trifluoromethyl, hydroxy,amino, methyl, ethyl and methoxy,

[0391] and wherein any heterocyclyl group within a substituent on R¹optionally bears 1 or 2 oxo substituents;

[0392] the Q¹-Z— group is selected from tetrahydrofuran-3-yloxy,tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy,pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy,3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy,piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy,2-piperidin-4-ylethoxy, 2-homopiperidin-1-ylethoxy,3-homopiperidin-1-ylpropoxy, homopiperidin-3-yloxy,homopiperidin-4-yloxy, homopiperidin-3-ylmethoxy,2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy,2-homopiperazin-1-ylethoxy or 3-homopiperazin-1-ylpropoxy,

[0393] and wherein any CH₂ or CH₃ group within the Q¹-Z— groupoptionally bears on each said CH₂ or CH₃ group a substituent selectedfrom hydroxy, amino, methoxy, methylsulphonyl, methylamino anddimethylamino,

[0394] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 substituents, which may be the same ordifferent, selected from fluoro, chloro, trifluoromethyl, hydroxy,amino, methyl, ethyl and methoxy,

[0395] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo substituents;

[0396] each of R² and R³ is hydrogen; and

[0397] Q² is an aryl group of formula la

[0398] wherein G¹ is selected from fluoro, chloro, bromo, iodo,trifluoromethyl, cyano, methyl, ethyl, vinyl, allyl, isopropenyl,ethynyl, methoxy and ethoxy, and each of G², G³, G⁴ and G⁵, which may bethe same or different, is selected from hydrogen, fluoro, chloro, bromo,trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl,isopropenyl, ethynyl, methoxy and ethoxy,

[0399] or G¹ and G² together form a group of formula: —CH═CH—CH═CH—,—O—CH═CH— or —O—CH₂—O—, and the 9- or 10-membered bicyclic heteroaryl orheterocyclic ring so formed optionally bears on the heteroaryl orheterocyclic portion of the bicyclic ring 1 or 2 substituents, which maybe the same or different, selected from fluoro, chloro, bromo,trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy, andany bicyclic heterocyclic ring so formed optionally bears 1 or 2 oxo orthioxo groups, and each of G³, G⁴ and G⁵, which may be the same ordifferent, is selected from hydrogen, fluoro, chloro, bromo,trifluoronmethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy;

[0400] or a pharmaceutically-acceptable acid-addition salt thereof.

[0401] A further preferred compound of the invention is a quinazolinederivative of the Formula I wherein:

[0402] m is 1 and the ¹e group is located at the 7-position and isselected from hydroxy, methoxy, ethoxy, propoxy, benzyloxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 2-hydroxyethoxy, 3-hydroxypropoxy,2-methoxyethoxy, 3-methoxypropoxy, 2-methylsulphonylethoxy,3-methylsulphonylpropoxy and 2-(2-methoxyethoxy)ethoxy;

[0403] and wherein any CH₂ group within a R¹ substituent that isattached to two carbon atoms optionally bears a hydroxy group on saidCH₂ group;

[0404] the Q¹-Z— group is selected from tetrahydrofuran-3-yloxy,tetrahydropyran-4-yloxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy,N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-yloxy, N-methylpiperidin-3-yloxy,piperidin-4-yloxy, N-methylpiperidin-4-yloxy, piperidin-3-ylmethoxy,N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy,N-methylpiperidin-4-ylmethoxy, 2-(4-methylpiperazin-1-yl)ethoxy and3-(4-methylpiperazin-1-yl)propoxy,

[0405] and wherein any CH₂ group within the Q¹-Z— group that is attachedto two carbon atoms optionally bears a hydroxy group on said CH,₂ group;

[0406] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo substituents;

[0407] each of R² and R³ is hydrogen; and

[0408] Q² is an aryl group of formula Ia

[0409] wherein G¹ is selected from fluoro, chloro, bromo, iodo,trifluoronmethyl, cyano, methyl, ethyl, vinyl, isopropenyl and ethynyl,each of G³ and G⁴, which may be the same or different, is selected fromhydrogen, fluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy,methyl, ethyl, vinyl, allyl, isopropenyl, ethynyl, methoxy and ethoxy,and each of G² and G⁵ is hydrogen, or G¹ and G² together form a group offormula: —CH═CH—CH═CH—, —O—CH═CH— or —O—CH₂—O—, and the 9- or10-membered bicyclic heteroaryl or heterocyclic ring so formedoptionally bears on the heteroaryl or heterocyclic portion of thebicyclic ring 1 or 2 substituents, which may be the same or different,selected from fluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy,methyl and methoxy, and each of G³, G⁴ and G⁵, which may be the same ordifferent, is selected from hydrogen, fluoro, chloro, bromo,trifluoromethyl, cyano, hydroxy, methyl and methoxy; or apharmaceutically-acceptable acid-addition salt thereof.

[0410] A further preferred compound of the invention is a quinazolinederivative of the Formula I wherein:

[0411] m is 1 and the R¹ group is located at the 7-position and isselected from hydroxy, methoxy, ethoxy, propoxy, benzyloxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1-,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy,2-[(2S)-2-(N-methylcarbamoyl)pyrrolidin-1-yl]ethoxy,2-[(2S)-2-(N,N-dimethylcarbamoyl)pyrrolidin-1-yl]ethoxy,2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 3-methoxypropoxy,2-methylsulphonylethoxy, 3-methylsulphonylpropoxy,2-(2-methoxyethoxy)ethoxy, 2-(4-pyridyloxy)ethoxy, 2-pyridylmethoxy,3-pyridylmethoxy and 4-pyridylmethoxy;

[0412] and wherein any CH₂ group within a R¹ substituent that isattached to two carbon atoms optionally bears a hydroxy group on saidCH₂ group;

[0413] the Q¹-Z— group is selected from tetrahydrofuran-3-yloxy,tetrahydropyran-4-yloxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy,N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 3-piperidinyloxy, N-methylpiperidin-3-yloxy,4-piperidinyloxy, N-methylpiperidin-4-yloxy, piperidin-3-ylmethoxy,N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy,N-methylpiperidin-4-ylmethoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, cyclobutyloxy, cyclopentyloxy andcyclohexyloxy,

[0414] and wherein any CH₂ group within the Q¹-Z— group that is attachedto two carbon atoms optionally bears a hydroxy group on said CH₂ group;

[0415] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo substituents;

[0416] each of R² and R³ is hydrogen; and

[0417] Q² is an aryl group of formula Ia

[0418] wherein G¹ is selected from fluoro, chloro, bromo, iodo,trifluoromethyl, cyano, methyl, ethyl, vinyl, isopropenyl, ethynyl,methoxy and pyrrolidin-1yl, G² is hydrogen, each of G³ and G⁴, which maybe the same or different, is selected from hydrogen, fluoro, chloro,bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl,isopropenyl, ethynyl, methoxy and ethoxy, and G⁵ is hydrogen or methoxy,

[0419] or G¹ and G²together form a group of formula: —CH═CH—CH═CH—,—O—CH═CH— or —O—CH₂—O—, and the 9- or 10-membered bicyclic heteroaryl orheterocyclic ring so formed optionally bears on the heteroaryl orheterocyclic portion of the bicyclic ring 1 or 2 substituents, which maybe the same or different, selected from fluoro, chloro, bromo,trifluoromethyl, cyano, hydroxy, methyl and methoxy, and each of G³, G⁴and G⁵, which may be the same or different, is selected from hydrogen,fluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl andmethoxy;

[0420] or a pharmaceutically-acceptable acid-addition salt thereof.

[0421] A further preferred compound of the invention is a quinazolinederivative of the Formula I wherein:

[0422] m is 1 and the R¹ group is located at the 7-position and isselected from hydroxy, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy,2-fluoroethoxy, 2,2,2-trifluoroethoxy, benzyloxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 2-piperidin-4-ylethoxy,2-(N-methylpiperidin-4-yl)ethoxy, 2-homopiperidin-1-ylethoxy,3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy,3-(4-cyanomethylpiperazin-1-yl)propoxy,2-[(2S)-2-carbamoylpyrrolidin-1-yl]ethoxy,2-[(2S)-2-(N-methylcarbamoyl)pyrrolidin-1-yl]ethoxy,2-[(2S)-2-(N,N-dimethylcarbamoyl)pyrrolidin-1-yl]ethoxy,2-tetrahydropyran-4-ylethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy,2-methoxyethoxy, 3-methoxypropoxy, 2-methylsulphonylethoxy,3-methylsulphonylpropoxy, 2-(2-methoxyethoxy)ethoxy,piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy,2-(4-pyridyloxy)ethoxy, 2-pyridylmethoxy, 3-pyridylmethoxy,4-pyridylmethoxy and 3-cyanopyrid-4-ylmethoxy;

[0423] and wherein any CH₂ group within a R¹ substituent that isattached to two carbon atoms optionally bears a hydroxy group on saidCH₂ group;

[0424] the Q¹-Z— group is selected from tetrahydrofuran-3-yloxy,tetrahydropyran-4-yloxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy,N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 3-piperidinyloxy, N-methylpiperidin-3-yloxy,4-piperidinyloxy, N-methylpiperidin-4-yloxy, piperidin-3-ylmethoxy,N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy,N-methylpiperidin-4-ylmethoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, cyclobutyloxy, cyclopentyloxy andcyclohexyloxy,

[0425] and wherein any CH₂ group within the Q¹-Z— group that is attachedto two carbon atoms optionally bears a hydroxy group on said CH₂ group;

[0426] and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo substituents;

[0427] each of R² and R³ is hydrogen; and

[0428] Q² is an aryl group of formula Ia

[0429] wherein G¹ is selected from fluoro, chloro, bromo, iodo,trifluoromethyl, cyano, methyl, ethyl, vinyl, isopropenyl, ethynyl,methoxy and pyrrolidin-1yl, G² is hydrogen, each of G³ and G⁴, which maybe the same or different, is selected from hydrogen, fluoro, chloro,bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl,isopropenyl, ethynyl, methoxy and ethoxy, and G⁵ is hydrogen or methoxy,

[0430] or G¹ and G² together form a group of formula: —CH═CH—CH═CH—,—O—CH═CH— or —O—CH₂—O—, and the 9- or 10-membered bicyclic heteroaryl orheterocyclic ring so formed optionally bears on the heteroaryl orheterocyclic portion of the bicyclic ring 1 or 2 substituents, which maybe the same or different, selected from fluoro, chloro, bromo,trifluoromethyl, cyano, hydroxy, methyl and methoxy, and each of G³, G⁴and G⁵, which may be the same or different, is selected from hydrogen,fluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl andmethoxy;

[0431] or a pharmaceutically-acceptable acid-addition salt thereof.

[0432] A further preferred compound of the invention is a quinazolinederivative of the Formula I wherein:

[0433] m is 1 and the R¹ group is located at the 7-position and isselected from hydroxy, methoxy, benzyloxy, 3-morpholinopropoxy,2-hydroxy-3-morpholinopropoxy, 3-(4-methylpiperazin-1-yl)propoxy,2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy, 2-methoxyethoxy and2-(2-methoxyethoxy)ethoxy;

[0434] the Q¹-Z— group is selected from tetrahydrofuran-3-yloxy,tetrahydropyran-4-yloxy, 3-pyrrolidin-1-ylpropoxy,N-methylpyrrolidin-3-yloxy, 3-morpholinopropoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,N-methylpiperidin-4-yloxy, piperidin-4-ylmethoxy,N-methylpiperidin-4-ylmethoxy and 3-(4-methylpiperazin-1-yl)propoxy,

[0435] each of R² and R³ is hydrogen; and

[0436] Q² is an aryl group of formula Ia

[0437] wherein G¹ is selected from fluoro, chloro, bromo and iodo, eachof G³ and G⁴, which may be the same or different, is selected fromhydrogen, chloro and methoxy, and each of G² and G⁵ is hydrogen,

[0438] or G¹ and G² together form a group of formula: —CH═CH—CH═C(Cl)—,—O—CH═C(Cl)— or —O—CH₂—O—, and each of G³, G⁴ and G⁵ is hydrogen;

[0439] or a pharmaceutically-acceptable acid-addition salt thereof.

[0440] A further preferred compound of the invention is a quinazolinederivative of the Formula I wherein:

[0441] m is 1 and the R¹ group is located at the 7-position and isselected from methoxy, benzyloxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,2-morpholinoethoxy, 3-morpholinopropoxy,2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy,2-[(2S)-2-(N-methylcarbamoyl)pyrrolidin-1-yl]ethoxy,2-[(2S)-2-(N,N-dimethylcarbamoyl)pyrrolidin-1-yl]ethoxy,3-methylsulphonylpropoxy, 2-(4-pyridyloxy)ethoxy, 2-pyridylmethoxy,3-pyridylmethoxy and 4-pyridylmethoxy;

[0442] the Q¹-Z— group is selected from tetrahydropyran-4-yloxy,3-pyrrolidin-1-ylpropoxy, N-methylpyrrolidin-3-yloxy,3-morpholinopropoxy, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy,2-piperidinoethoxy, 4-piperidinyloxy, N-methylpiperidin-4-yloxy,piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy,3-(4-methylpiperazin-1-yl)propoxy, cyclopentyloxy and cyclohexyloxy;

[0443] each of R² and R³ is hydrogen; and

[0444] Q² is an aryl group of formula Ia

[0445] wherein G¹ is selected from chloro, bromo, trifluoronmethyl,methyl, methoxy and pyrrolidin-1-yl, G² is hydrogen, G³ is selected fromhydrogen and chloro, G⁴ is methoxy, and G⁵ is hydrogen,

[0446] or G¹ and G² together form a group of formula: —CH═CH—CH═C(Cl)—,—O—CH═C(Cl)  or —O—CH₂—O—, each of G³ and G⁴ is hydrogen, and G⁵ ishydrogen or chloro;

[0447] or a pharmaceutically-acceptable acid-addition salt thereof.

[0448] A further preferred compound of the invention is a quinazolinederivative of the Formula I wherein:

[0449] m is 1 and the R¹ group is located at the 7-position and isselected from methoxy, ethoxy, propoxy, isopropoxy, isobutoxy,2-fluoroethoxy, 2,2,2-trifluoroethoxy, benzyloxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 2-piperidin-4-ylethoxy,2-(N-methylpiperidin-4-yl)ethoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy,2-homopiperidin-1-ylethoxy, 3-homopiperidin-1-ylpropoxy,2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy,2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy,3-(4-cyanomethylpiperazin-1-yl)propoxy,2-[(2S)-2-carbamoylpyrrolidin-1-yl]ethoxy,2-[(2S)-2-(N-methylcarbamoyl)pyrrolidin-1-yl]ethoxy,2-[(2S)-2-(N,N-dimethylcarbamoyl)pyrrolidin-1-yl]ethoxy,3-methylsulphonylpropoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-(4-pyridyloxy)ethoxy, 2-pyridylmethoxy,3-pyridylmethoxy, 4-pyridylmethoxy and 2-cyanopyrid-4-ylmethoxy,

[0450] and wherein any CH₂ group within a R¹ substituent that isattached to two carbon atoms optionally bears a hydroxy group on saidCH₂ group;

[0451] the Q¹-Z— group is selected from tetrahydropyran-4-yloxy,3-pyrrolidin-1-ylpropoxy, N-methylpyrrolidin-3-yloxy,3-morpholinopropoxy, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy,2-piperidinoethoxy, 4-piperidinyloxy, N-methylpiperidin-4-yloxy,piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy,3-(4-methylpiperazin-1-yl)propoxy, cyclopentyloxy and cyclohexyloxy;

[0452] each of R² and R³ is hydrogen; and

[0453] Q ² is an aryl group of formula Ia

[0454] wherein G¹ is selected from chloro, bromo, trifluoromethyl,methyl, methoxy and pyrrolidin-1-yl, G² is hydrogen, G³ is selected fromhydrogen and chloro, G⁴ is methoxy, and G⁵ is hydrogen,

[0455] or G¹ and G² together form a group of formula: —O—CH═CH—,—O—CH═C(Cl)— or —O—CH₂—O—, each of G³ and G⁴ is hydrogen, and G⁵ ishydrogen or chloro;

[0456] or a pharmaceutically-acceptable acid-addition salt thereof.

[0457] A further preferred compound of the invention is a quinazolinederivative of the Formula I wherein:

[0458] m is 1 and the R¹ group is located at the 7-position and isselected from methoxy, benzyloxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,2-morpholinoethoxy, 3-morpholinopropoxy,2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy,2-[(2S)-2-(N-methylcarbamoyl)pyrrolidin-(1-yl]ethoxy,2-[(2S)-2-(N,N-dimethylcarbamoyl)pyrrolidin-1-yl]ethoxy,3-methylsulphonylpropoxy, 2-(4-pyridyloxy)ethoxy, 2-pyridylmethoxy,3-pyridylmethoxy and 4-pyridylmethoxy;

[0459] the Q¹-Z— group is selected from tetrahydropyran-4-yloxy,4-piperidinyloxy, N-methylpiperidin-4-yloxy, cyclopentyloxy andcyclohexyloxy;

[0460] each of R² and R³ is hydrogen; and

[0461] Q² is an aryl group of formula Ia

[0462] wherein G¹ and G² together form a group of formula: —O—CH₂—O—,each of G³ and G⁴ is hydrogen, and G⁵ is chloro;

[0463] or a pharmaceutically-acceptable acid-addition salt thereof.

[0464] A further preferred compound of the invention is a quinazolinederivative of the Formula I wherein:

[0465] m is 1 and the R¹ group is located at the 7-position and isselected from methoxy, ethoxy, propoxy, isopropoxy, isobutoxy,2-fluoroethoxy, 2,2,2-trifluoroethoxy, benzyloxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 3-(4-hydroxypiperidin-1-yl)propoxy,2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy,2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy,3-(4-cyanomethylpiperazin-1-yl)propoxy,2-[(2S)-2-carbamoylpyrrolidin-1-yl]ethoxy,2-[(2S)-2-N-methylcarbamoyl)pyrrolidin-1-yl]ethoxy,2-[(2S)-2-(N,N-dimethylcarbamoyl)pyrrolidin-1-yl]ethoxy,3-methylsulphonylpropoxy, piperidin-4-ylmethoxy,N-methylpiperidin-4-ylmethoxy, 2-(4-pyridyloxy)ethoxy, 2-pyridylmethoxy,3-pyridylmethoxy and 4-pyridylmethoxy;

[0466] the Q¹-Z— group is selected from tetrahydropyran-4-yloxy,4-piperidinyloxy, N-methylpiperidin-4-yloxy, piperidin-4-ylmethoxy,N-methylpiperidin-4-ylmethoxy, cyclopentyloxy and cyclohexyloxy;

[0467] each of R² and R³ is hydrogen; and

[0468] Q² is an aryl group of formula Ia

[0469] wherein G¹ and G² together form a group of formula: —O—CH₂—O—,each of G³ and G⁴ is hydrogen, and G⁵ is chloro;

[0470] or a pharmaceutically-acceptable acid-addition salt thereof.

[0471] A particular preferred compound of the invention is, for example,a quinazoline derivative of the Formula I selected from:

[0472]4-(2-chloro-5-methoxyanilino)-5,7-di-(3-morpholinopropoxy)quinazoline,

[0473]4-(2-bromo-5-methoxyanilino)-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline,

[0474]4-(2-chloro-5-methoxyanilino)-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline,

[0475]4-(2-chloro-5-methoxyanilino)-7-[3-(4-methylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazoline,

[0476]4-(2-chloro-5-methoxyanilino)-7-(3-morpholinopropoxy)-5-tetrahydropyran-4-yloxyquinazoline,

[0477]4-(2-chloro-5-methoxyanilino)-7-[2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazoline,

[0478]4-(2-chloro-5-methoxyanilino)-7-(2-hydroxy-3-morpholinopropoxy)-5-tetrahydropyran-4-yloxyquinazoline,

[0479]4-(2-chloro-5-methoxyanilino)-7-[3-(4-methylpiperazin-1-yl)propoxy]-5-tetrahydrofuran-3-yloxyquinazoline,

[0480]4-(2-chloro-5-methoxyanilino)-7-(3-morpholinopropoxy)-5-tetrahydrofuran-3-yloxyquinazoline,

[0481]4-(5-chloronaphth-1-ylamino)-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazolineand

[0482]4-(3-chlorobenzofuran-7-ylamino)-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline,

[0483] or a pharmaceutically-acceptable acid-addition salt thereof.

[0484] A further particular preferred compound of the invention is, forexample, a quinazoline derivative of the Formula I selected from:

[0485]4-(2-chloro-5-methoxyanilino)-5-isopropoxy-7-(3-morpholinopropoxy)quinazolineand

[0486]4-(2-chloro-5-methoxyanilino)-5-isopropoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline,

[0487] or a pharmaceutically-acceptable acid-addition salt thereof.

[0488] A particular preferred compound of the invention is, for example,a quinazoline derivative of the Formula I selected from:

[0489]7-benzyloxy-4-(2-bromo-5-methoxyanilino)-5-piperidin-4-yloxyquinazoline,

[0490]4-(2-bromo-5-methoxyanilino)-7-(3-methylsulphonylpropoxy)-5-piperidin-4-yloxyquinazoline,

[0491]4-(2-bromo-5-methoxyanilino)-7-methoxy-5-piperidin-4-ylmethoxyquinazoline,

[0492]4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline,

[0493]4-(2,5-dimethoxyanilino)-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline,

[0494]4-(2,4-dichloro-5-methoxyanilino)-7-(2-pyrrolidin-1-ylethoxy)-5-tetrahydropyran-4-yloxyquinazoline,

[0495]4-(2,4-dichloro-5-methoxyanilino)-7-(2-piperidinoethoxy)-5-tetrahydropyran-4-yloxyquinazoline,

[0496]4-(2,4-dichloro-5-methoxyanilino)-7-(2-morpholinoethoxy)-5-tetrahydopyran-4-yloxyquinazoline,

[0497]4-(2,4-dichloro-5-methoxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline,

[0498]4-(2-bromo-5-methoxyanilino)-7-(2-pyrrolidin-1-ylethoxy)-5-tetrahydropyran-4-yloxyquinazoline,

[0499]4-(2-bromo-5-methoxyanilino)-7-(2-piperidinoethoxy)-5-tetrahydropyran-4-yloxyquinazoline,

[0500]4-(2-bromo-5-methoxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline,

[0501]4-(2-bromo-5-methoxyanilino)-7-(4-pyridyloxyethoxy)-5-tetrahydropyran-4-yloxyquinazoline,

[0502]4-(2-bromo-5-methoxyanilino)-7-{2-[(2S)-2-(N,N-dimethylcarbamoyl)pyrrolidin-1-yl]ethoxy}-5-tetrahydropyran-4-yloxyquinazoline,

[0503]4-(2-bromo-5-methoxyanilino)-7-{2-[(2S)-2-(N-methylcarbamoyl)pyrrolidin-1-yl]ethoxy}-5-tetrahydropyran-4-yloxyquinazoline,

[0504]4-(2-bromo-5-methoxyanilino)-7-(4-pylidylmethoxy)-5-tetrahydropyran-4-yloxyquinazoline,

[0505]4-(5-methoxy-2-pyrrolidin-1-ylanilino)-7-[3-(4-methylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazoline,and

[0506]4-(2-bromo-5-methoxyanilino)-5-cyclopentyloxy-7-(2-pyrrolidin-1-ylethoxy)quinazoline;

[0507] or a pharmaceutically-acceptable acid-addition salt thereof.

[0508] A further particular preferred compound of the invention is, forexample, a quinazoline derivative of the Formula I selected from:

[0509]4-(6-chloro-2,3-methylenedioxyanilino)-5-cyclopentyloxy-7-(2-pyrrolidin-1-ylethoxy)quinazoline,

[0510]4-(6-chloro-2,3-methylenedioxyanilno)-5-piperidin-4-yloxyquinazoline,

[0511]4-(6-chloro-2,3-methylenedioxyanilno)-7-methoxy-5-piperidin-4-yloxyquinazoline,

[0512]4-(6-chloro-2,3-methylenedioxyanilino)-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline,

[0513]4-(6-chloro-2,3-methylenedioxyanilno)-7-methoxy-5-piperidin-4-ylmethoxyquinazoline,

[0514]4-(6-chloro-2,3-methylenedioxyanilino)-7-(2-pyrrolidin-1-ylethoxy)-5-tetrahydropyran-4-yloxyquinazoline,

[0515]4-(6-chloro-2,3-methylenedioxyanilino)-7-(3-pyrrolidin-1-ylpropoxy)-5-tetrahydropyran-4-yloxyquinazoline,

[0516]4-(6-chloro-2,3-methylenedioxyanilino)-7-[3-(4-methylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazoline,

[0517]4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline,

[0518]4-(6-chloro-2,3-methylenedioxyanilino)-7-(2-piperidinoethoxy)-5-tetrahydropyran-4-yloxyquinazoline,

[0519]4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-pyridyloxy)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline,

[0520]4-(6-chloro-2,3-methylenedioxyanilino)-7-piperidin-4-ylmethoxy-5-tetrahydropyran-4-yloxyquinazolineand

[0521]4-(6-choro-2,3-methylenedioxyanilno)-7-(N-methylpiperidin-4-ylmethoxy)-5-tetrahydropyran-4-yloxyquinazoline;

[0522] or a pharmaceutically-acceptable acid-addition salt thereof.

[0523] A quinazoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, may be prepared by any processknown to be applicable to the preparation of chemically-relatedcompounds. Such processes, when used to prepare a quinazoline derivativeof the Formula I are provided as a further feature of the invention andare illustrated by the following representative process variants inwhich, unless otherwise stated, Q¹, Z, m, R¹, R², R³ and Q² have any ofthe meanings defined hereinbefore. Necessary starting materials may beobtained by standard procedures of organic chemistry. The preparation ofsuch starting materials is described in conjunction with the followingrepresentative process variants and within the accompanying Examples.Alternatively necessary starting materials are obtainable by analogousprocedures to those illustrated which are within the ordinary skill ofan organic chemist.

[0524] (a) The reaction, conveniently in the presence of a suitablebase, of a quinazoline of the Formula II

[0525] wherein L is a displaceable group and Q¹, Z, m, R¹ and R² haveany of the meanings defined hereinbefore except that any functionalgroup is protected if necessary, with an aniline of the Formula

Q²NHR³

[0526] wherein Q² and R³ have any of the meanings defined hereinbeforeexcept that any functional group is protected if necessary, whereafterany protecting group that is present is removed by conventional means.

[0527] A suitable base is, for example, an organic amine base such as,for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, morpholine, N-methylmorpholine ordiazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkalineearth metal carbonate or hydroxide, for example sodium carbonate,potassium carbonate, calcium carbonate, sodium hydroxide or potassiumhydroxide, or, for example, an alkali metal hydride, for example sodiumhydride.

[0528] A suitable displaceable group L is, for example, a halogeno,alkoxy, aryloxy or sulphonyloxy group, for example a chloro, bromo,methoxy, phenoxy, pentafluorophenoxy, methanesulphonyloxy ortoluene-4-sulphonyloxy group. The reaction is conveniently carried outin the presence of a suitable inert solvent or diluent, for example analcohol or ester such as methanol, ethanol, isopropanol or ethylacetate, a halogenated solvent such as methylene chloride, chloroform orcarbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, anaromatic solvent such as toluene, or a dipolar aprotic solvent such asN,N-dimethylfolmamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-oneor dimethylsulphoxide. The reaction is conveniently carried out at atemperature in the range, for example, 10 to 250° C., preferably in therange 40 to 80° C.

[0529] Typically, the quinazoline of the Formula II may be reacted withan aniline of the formula Q²NHR³ in the presence of a protic solventsuch as isopropanol, conveniently in the presence of an acid, forexample hydrogen chloride gas in diethyl ether, or hydrochloric acid,and at a temperature in the range, for example, 0 to 150° C., preferablyat or near the reflux temperature of the reaction solvent.

[0530] The quinazoline derivative of the Formula I may be obtained fromthis process in the form of the free base or alternatively it may beobtained in the form of a salt with the acid of the formula H-L whereinL has the meaning defined hereinbefore. When it is desired to obtain thefree base from the salt, the salt may be treated with a suitable base,for example, an organic amine base such as, for example, pyridine,2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or,for example, an alkali or alkaline earth metal carbonate or hydroxide,for example sodium carbonate, potassium carbonate, calcium carbonate,sodium hydroxide or potassium hydroxide.

[0531] Protecting groups may in general be chosen from any of the groupsdescribed in the literature or known to the skilled chemist asappropriate for the protection of the group in question and may beintroduced by conventional methods. Protecting groups may be removed byany convenient method as described in the literature or known to theskilled chemist as appropriate for the removal of the protecting groupin question, such methods being chosen so as to effect removal of theprotecting group with minimum disturbance of groups elsewhere in themolecule.

[0532] Specific examples of protecting groups are given below for thesake of convenience, in which “lower”, as in, for example, lower alkyl,signifies that the group to which it is applied preferably has 1-4carbon atoms. It will be understood that these examples are notexhaustive. Where specific examples of methods for the removal ofprotecting groups are given below these are similarly not exhaustive.The use of protecting groups and methods of deprotection notspecifically mentioned are, of course, within the scope of theinvention.

[0533] A carboxy protecting group may be the residue of an ester-formingaliphatic or arylaliphatic alcohol or of an ester-forming silanol (thesaid alcohol or silanol preferably containing 1-20 carbon atoms).Examples of carboxy protecting groups include straight or branched chain(1-12C)alkyl groups (for example isopropyl, and tert-butyl); loweralkoxy-lower alkyl groups (for example methoxymethyl, ethoxymethyl andisobutoxymethyl); lower acyloxy-lower alkyl groups, (for exampleacetoxymethyl, propionyloxymethyl, butyryloxymethyl andpivaloyloxymethyl); lower alkoxycarbonyloxy-lower alkyl groups (forexample 1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl);aryl-lower alkyl groups (for example benzyl, 4-methoxybenzyl,2-nitrobenzyl, 4-nitrobenzyl, benzhydryl and phthalidyl); tri(loweralkyl)silyl groups (for example trimethylsilyl andtert-butyldimethylsilyl); tri(lower alkyl)silyl-lower alkyl groups (forexample trimethylsilylethyl); and (2-6C)alkenyl groups (for exampleallyl). Methods particularly appropriate for the removal of carboxylprotecting groups include for example acid-, base-, metal- orenzymically-catalysed cleavage.

[0534] Examples of hydroxy protecting groups include lower alkyl groups(for example tert-butyl), lower alkenyl groups (for example allyl);lower alkanoyl groups (for example acetyl); lower alkoxycarbonyl groups(for example tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (forexample allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for examplebenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyland 4-nitrobenzyloxycarbonyl); tri(lower alkyl)silyl (for exampletrimethylsilyl and tert-butyldimethylsilyl) and aryl-lower alkyl (forexample benzyl) groups.

[0535] Examples of amino protecting groups include formyl, aryl-loweralkyl groups (for example benzyl and substituted benzyl,4-methoxybenzyl, 2-nitrobenzyl and 2,4-dimethoxybenzyl, andtriphenylmethyl); di-4-anisylmethyl and furylmethyl groups; loweralkoxycarbonyl (for example tert-butoxycarbonyl); loweralkenyloxycarbonyl (for example allyloxycarbonyl); aryl-loweralkoxycarbonyl groups (for example benzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and4-nitrobenzyloxycarbonyl); trialkylsilyl (for example trimethylsilyl andtert-butyldimethylsilyl); alkylidene (for example methylidene) andbenzylidene and substituted benzylidene groups.

[0536] Methods appropriate for removal of hydroxy and amino protectinggroups include, for example, acid-, base-, metal- orenzymically-catalysed hydrolysis for groups such as2-nitrobenzyloxycarbonyl, hydrogenation for groups such as benzyl andphotolytically for groups such as 2-nitrobenzyloxycarbonyl.

[0537] The reader is referred to Advanced Organic Chemistry, 4thEdition, by J. March, published by John Wiley & Sons 1992, for generalguidance on reaction conditions and reagents and to Protective Groups inOrganic Synthesis, 2^(nd) Edition, by T. Green et al., also published byJohn Wiley & Son, for general guidance on protecting groups.

[0538] Quinazoline starting materials of the Formula II may be obtainedby conventional procedures. For example, a 3,4-dihydroquinazolin-4-oneof Formula III

[0539] wherein m, R¹, Q¹, Z and R² have any of the meanings definedhereinbefore except that any functional group is protected if necessary,may be reacted with a halogenating agent such as thionyl chloride,phosphoryl chloride or a mixture of carbon tetrachloride andtriphenylphosphine whereafter any protecting group that is present isremoved by conventional means.

[0540] The 4-chloroquinazoline so obtained may be converted, ifrequired, into a 4-pentafluorophenoxyquinazoline by reaction withpentafluorophenol in the presence of a suitable base such as potassiumcarbonate and in the presence of a suitable solvent such asN,N-dimethylformamide.

[0541] (b) For the production of those compounds of the Formula Iwherein Z is an oxygen atom, the coupling, conveniently in the presenceof a suitable dehydrating agent, of an alcohol of the Formula

Q¹-OH

[0542] wherein Q¹ has any of the meanings defined hereinbefore exceptthat any functional group is protected if necessary with a quinazolineof the Formula IV

[0543] wherein m, R¹, R², R³ and Q² have any of the meanings definedhereinbefore except that any functional group is protected if necessary,whereafter any protecting group that is present is removed byconventional means.

[0544] A suitable dehydrating agent is, for example, a carbodiimidereagent such as dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or a mixture of an azocompound such as diethyl or di-tert-butyl azodicarboxylate and aphosphine such as triphenylphosphine. The reaction is convenientlycarried out in the presence of a suitable inert solvent or diluent, forexample a halogenated solvent such as methylene chloride, chloroform orcarbon tetrachloride and at a temperature in the range, for example, 10to 150° C., preferably at or near ambient temperature.

[0545] The quinazoline of the Formula IV may be obtained by conventionalprocedures. For example, a quinazoline of the Formula V

[0546] wherein L is a displaceable group as defined hereinbefore and m,R¹ and R² have any of the meanings defined hereinbefore except that anyfunctional group is protected if necessary, may be reacted with ananiline of the Formula

Q²NHR³

[0547] wherein Q² and R³ have any of the meanings defined hereinbeforeexcept that any functional group is protected if necessary, whereafterany protecting group that is present is removed by conventional means.

[0548] (c) For the production of those compounds of the Formula Iwherein m is 1 and R¹ is a group of the formula

Q³-X¹—

[0549] wherein Q³ is an aryl-(1-6C)alkyl, (3-7C)cycloalkyl-(1-6C)alkyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl-(1-6C)alkyl orheterocyclyl-(1-6C)alkyl group and X¹ is an oxygen atom, the coupling,conveniently in the presence of a suitable dehydrating agent as definedhereinbefore, of a quinazoline of the Formula VI

[0550]

[0551] wherein Q¹, Z, R², R³ and Q² have any of the meanings definedhereinbefore except that any functional group is protected if necessary,with an appropriate alcohol wherein any functional group is protected ifnecessary, whereafter any protecting group that is present is removed byconventional means.

[0552] The reaction is conveniently carried out in the presence of asuitable inert solvent or diluent, for example a halogenated solventsuch as methylene chloride, chloroform or carbon tetrachloride and at atemperature in the range, for example, 10 to 150° C., preferably at ornear ambient temperature.

[0553] (d) For the production of those compounds of the Formula Iwherein R¹ is a hydroxy group, the cleavage of a quinazoline derivativeof the Formula I wherein R¹ is a (1-6C)alkoxy or arylmethoxy group.

[0554] The cleavage reaction may conveniently be carried out by any ofthe many procedures known for such a transformation. The cleavagereaction of a compound of the Formula I wherein R¹ is a (1-6C)alkoxygroup may be carried out, for example, by treatment of the quinazolinederivative with an alkali metal (1-6C)alkylsulphide such as sodiumethanethiolate or, for example, by treatment with an alkali metaldiarylphosphide such as lithium diphenylphosphide. Alternatively thecleavage reaction may conveniently be carried out, for example, bytreatment of the quinazoline derivative with a boron or aluminiumtrihalide such as boron tribromide. The cleavage reaction of a compoundof the Formula I wherein R¹ is a arylmethoxy group may be carried out,for example, by hydrogenation of the quinazoline derivative in thepresence of a suitable metallic catalyst such as palladium or byreaction with an organic or inorganic acid, for example trifluoroaceticacid. Such reactions are preferably carried out in the presence of asuitable inert solvent or diluent as defined hereinbefore and at atemperature in the range, for example, 10 o 150° C., preferably at ornear ambient temperature.

[0555] (e) For the production of those compounds of the Formula Iwherein Q¹, R¹ or Q² contains a primary or secondary amino group, thecleavage of the corresponding compound of Formula I wherein Q¹, R¹ or Q²contains a protected primary or secondary amino group.

[0556] Suitable protecting groups for an amino group are, for example,any of the protecting groups disclosed hereinbefore for an amino group.Suitable methods for the cleavage of such amino protecting groups arealso disclosed hereinbefore. In particular, a suitable protecting groupis a lower alkoxycarbonyl group such as a tert-butoxycarbonyl groupwhich may be cleaved under conventional reaction conditions such asunder acid-catalysed hydrolysis, for example in the presence oftrifluoroacetic acid.

[0557] (f) For the production of those compounds of the Formula Iwherein Q¹, R¹ or Q² contains a (1-6C)alkoxy or substituted (1-6C)alkoxygroup or a (1-6C)alkylamino or substituted (1-6C)alkylamino group, thealkylation, conveniently in the presence of a suitable base as definedhereinbefore, of a quinazoline derivative of the formula I wherein Q¹,R¹ or Q² contains a hydroxy group or a primary or secondary amino groupas appropriate.

[0558] A suitable alkylating agent is, for example, any agent known inthe art for the alkylation of hydroxy to alkoxy or substituted alkoxy,or for the alkylation of amino to alkylamino or substituted alkylamino,for example an alkyl or substituted alkyl halide, for example a(1-6C)alkyl chloride, bromide or iodide or a substituted (1-6C)alkylchloride, bromide or iodide, conveniently in the presence of a suitablebase as defined hereinbefore, in a suitable inert solvent or diluent asdefined hereinbefore and at a temperature in the range, for example, 10to 140° C., conveniently at or near ambient temperature.

[0559] Conveniently for the production of those compounds of the FormulaI wherein Q¹, R¹ or Q² contains a (1-6C)alkylamino or substituted(1-6C)alkylamino group, a reductive amination reaction may be employed.For example, for the production of those compounds of the Formula Iwherein Q¹, R¹ or Q² contains a N-methyl group, the correspondingcompound containing a N—H group may be reacted with formaldehyde in thepresence of a suitable reducing agent. A suitable reducing agent is, forexample, a hydride reducting agent, for example an alkali metalaluminium hydride such as lithium aluminium hydride or, preferably, analkali metal borohydride such as sodium borohydride, sodiumcyanoborohydride, sodium triethylborohydride, sodiumtrimethoxyborohydride and sodium triacetoxybdrohydride. The reaction isconveniently performed in a suitable inert solvent or diluent, forexample tetrahydrofuran and diethyl ether for the more powerful reducingagents such as lithium aluminium hydride, and, for example, methylenechloride or a protic solvent such as methanol and ethanol for the lesspowerful reducing agents such as sodium triacetoxyborohydride and sodiumcyanoborohydride. The reaction is performed at a temperature in therange, for example, 10 to 80° C., conveniently at or near ambienttemperature.

[0560] (g) For the production of those compounds of the Formula Iwherein Q¹, R¹ or Q² contains an amino-hydroxy-disubstituted(1-6C)alkoxy group (such as 2-hydroxy-3-piperidinopropoxy,2-hydroxy-3-methylaminopropoxy, 3-dimethylamino-2-hydroxypropoxy or3-[N-(3-dimethylaminopropyl)-N-methylamino]-2-hydroxypropoxy), thereaction of a compound of the Formula I wherein Q¹, R¹ or Q² contains anepoxy-substituted (1-6C)alkoxy group with a heterocyclyl compound or anappropriate amine.

[0561] The reaction is conveniently carried out in the presence of asuitable inert diluent or carrier as defined hereinbefore and at atemperature in the range 10 to 150° C., preferably at or near ambienttemperature.

[0562] (h) The reaction, conveniently in the presence of a suitable baseas defined hereinbefore, of a quinazoline of the Formula VII

[0563] wherein L is a displaceable group as defined hereinbefore and m,R¹, R², R³ and Q¹ have any of the meanings defined hereinbefore exceptthat any functional group is protected if necessary, with a compound ofthe Formula

Q¹ZH

[0564] wherein Q¹ and Z have any of the meanings defined hereinbeforeexcept that any functional group is protected if necessary, whereafterany protecting group that is present is removed by conventional means.

[0565] The reaction is conveniently carried out in the presence of asuitable inert diluent or carrier as defined hereinbefore and at atemperature in the range 10 to 150° C., preferably at or near 50° C.

[0566] (i) For the production of those compounds of the Formula Iwherein Q¹, R¹ or Q² contains an amino-substituted (1-6C)alkoxy group(such as 3-piperidinopropoxy, 3-methylaminopropoxy or3-dimethylaminopropoxy), the reaction of a compound of the Formula Iwherein Q¹, R¹ or Q² contains a halogeno-substituted (1-6C)alkoxy groupwith a heterocyclyl compound or an appropriate amine.

[0567] The reaction is conveniently carried out in the presence of asuitable inert diluent or carrier as defined hereinbefore and at atemperature in the range 10 to 150° C., preferably at or near ambienttemperature.

[0568] When a pharmaceutically-acceptable salt of a quinazolinederivative of the Formula I is required, for example an acid-additionsalt, it may be obtained by, for example, reaction of said quinazolinederivative with a suitable acid using a conventional procedure.

[0569] Biological Assays

[0570] The following assays can be used to measure the effects of thecompounds of the present invention as c-Src tyrosine kinase inhibitors,as inhibitors in vitro of the proliferation of c-Src transfectedfibroblast cells, as inhibitors in vitro of the migration of A549 humanlung tumour cells and as inhibitors in vivo of the growth in nude miceof xenografts of A549 tissue.

[0571] (a) In Vitro Enzyme Assay

[0572] The ability of test compounds to inhibit the phosphorylation of atyrosine containing polypeptide substrate by the enzyme c-7Src kinasewas assessed using a conventional Elisa assay.

[0573] A substrate solution [100 μl of a 20 μg/ml solution of thepolyamino acid Poly(Glu, Tyr) 4:1 (Sigma Catalogue No. P0275) inphosphate buffered saline (PBS) containing 0.2 mg/ml of sodium azide]was added to each well of a number of Nunc 96-well immunoplates(Catalogue No. 439454) and the plates were sealed and stored at 4° C.for 16 hours. The excess of substrate solution was discarded, andaliquots of Bovine Serum Albumin (BSA; 150 μl of a 5% solution in PBS)were transferred into each substrate-coated assay well and incubated for1 hour at ambient temperature to block non specific binding. The assayplate wells were washed in turn with PBS containing 0.05% v/v Tween 20(PBST) and with Hepes pH7.4 buffer (50 mM, 300 μl/well) before beingblotted dry.

[0574] Each test compound was dissolved in dimethyl sulphoxide anddiluted with distilled water to give a series of dilutions (from 100 μMto 0.001 μM). Portions (25 μl) of each dilution of test compound weretransferred to wells in the washed assay plates. “Total” control wellscontained diluted DMSO instead of compound. Aliquots (25 μl) of anaqueous magnesium chloride solution (80 mM) containingadenosine-5′-triphosphate (ATP; 40 μM) was added to all test wellsexcept the “blank” control wells which contained magnesium chloridewithout ATP.

[0575] Active human c-Src kinase (recombinant enzyme expressed in Sf9insect cells; obtained from Upstate Biotechnology Inc. product 14-117)was diluted immediately prior to use by a factor of 1:10,000 with anenzyme diluent which comprised 100 mM Hepes pH7.4 buffer, 0.2 mM sodiumorthovanadate, 2 mM dithiothreitol and 0.02% BSA. To start thereactions, aliquots (50 μl) of freshly diluted enzyme were added to eachwell and the plates were incubated at ambient temperature for 20minutes. The supernatant liquid in each well was discarded and the wellswere washed twice with PBST. Mouse IgG anti-phosphotyrosine antibody(Upstate Biotechnology Inc. product 05-321; 100 μl) was diluted by afactor of 1:6000 with PBST containing 0.5% w/v BSA and added to eachwell. The plates were incubated for 1 hour at ambient temperature. Thesupernatant liquid was discarded and each well was washed with PBST(×4). Horse radish peroxidase (HRP)-linked sheep anti-mouse Ig antibody(Amersham Catalogue No. NXA 931; 100 μl) was diluted by a factor of1:500 with PBST containing 0.5% w/v BSA and added to each well. Theplates were incubated for 1 hour at ambient temperature. The supernatantliquid was discarded and the wells were washed with PBST (×4).

[0576] A PCSB capsule (Sigma Catalogue No. P4922) was dissolved indistilled water (100 ml) to provide phosphate-citrate pH5 buffer (50 mM)containing 0.03% sodium perborate. An aliquot (50 μl) of this buffer wasmixed with a 50 mg tablet of2,2′-azinobis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS; BoehringerCatalogue No. 1204 521). Aliquots (100 μl) of the resultant solutionwere added to each well. The plates were incubated for 20 to 60 minutesat ambient temperature until the optical density value of the “total”control wells, measured at 405 nm using a plate readingspectrophotometer, was approximately 1.0. “Blank” (no ATP) and “total”(no compound) control values were used to determine the dilution rangeof test compound which gave 50% inhibition of enzyme activity.

[0577] (b) In Vitro c-Src Transfected NIH 3T3 (c-src 3T3) FibroblastProliferation Assay

[0578] This assay determined the ability of a test compound to inhibitthe proliferation of National Institute of Health (NIH) mouse 3T3fibroblast cells that had been stably-transfected with an activatingmutant (Y530F) of human c-Src.

[0579] Using a similar procedure to that described by Shalloway et al.,Cell, 1987, 49, 65-73, NIH 3T3 cells were transfected with an activatingmutant (Y530F) of human c-Src. The resultant c-Src 3T3 cells weretypically seeded at 1.5×10⁴ cells per well into 96-welltissue-culture-treated clear assay plates (Costar) each containing anassay medium comprising Dulbecco's modified Eagle's medium (DMEM; Sigma)plus 0.5% foetal calf serum (FCS), 2 mM glutamine, 100 units/mlpenicillin and 0.1 mg/ml streptomycin in 0.9% aqueous sodium chloridesolution. The plates were incubated overnight at 37° C. in a humidified(7.5% CO₂: 95% air) incubator.

[0580] Test compounds were solubilised in DMSO to form a 10 mM stocksolution. Aliquots of the stock solution were diluted with the DMEMmedium described above and added to appropriate wells. Serial dilutionswere made to give a range of test concentrations. Control wells to whichtest compound was not added were included on each plate. The plates wereincubated overnight at 37° C. in a humidified (7.5% CO₂: 95% air)incubator.

[0581] BrdU labelling reagent (Boehringer Mannheim Catalogue No. 647229) was diluted by a factor of 1:100 in DMEM medium containing 0.5% FCSand aliquots (20 μl) were added to each well to give a finalconcentration of 10 μM). The plates were incubated at 37° C. for 2hours. The medium was decanted. A denaturating solution (FixDenatsolution, Boehringer Mannheim Catalogue No. 647 229; 50 μl) was added toeach well and the plates were placed on a plate shaker at ambienttemperature for 45 minutes. The supernatant was decanted and the wellswere washed with PBS (200 μl per well). Anti-BrdU-Peroxidase solution(Boehringer Mannheim Catalogue No. 647 229) was diluted by a factor of1:100 in PBS containing 1% BSA and 0.025% dried skimmed milk (Marvel(registered trade mark), Premier Beverages, Stafford, GB) and an aliquot(100 μl ) of the resultant solution was added to each well. The plateswere were placed on a plate shaker at ambient temperature for 90minutes. The wells were washed with PBS (×5) to ensure removal of nonbound antibody conjugate. The plates were blotted dry andtetramethylbenzidine substrate solution (Boehringer Mannheim CatalogueNo. 647 229; 100 μl) was added to each well. The plates were gentlyagitated on a plate shaker while the colour developed during a 10 to 20minute period. The absorbance of the wells was measured at 690 nm. Theextent of inhibition of cellular proliferation at a range ofconcentrations of each test compound was determined and ananti-proliferative IC₅₀ value was derived.

[0582] (c) In Vitro Microdroplet Migration Assay

[0583] This assay determines the ability of a test compound to inhibitthe migration of adherent mammalian cell lines, for example the humantumour cell line A549.

[0584] RPMI medium(Sigma) containing 10% FCS, 1% L-glutamine and 0.3%agarose (Difco Catalogue No. 0142-01) was warmed to 37° C. in awaterbath. A stock 2% aqueous agar solution was autoclaved and stored at42° C. An aliquot (1.5 ml) of the agar solution was added to RPMI medium(10 ml) immediately prior to its use. A549 cells (Accession No. ATCCCCL185) were suspended at a concentration of 2×10⁷ cells/ml in themedium and maintained at a temperature of 37° C.

[0585] A droplet (2 μl) of the cell/agarose mixture was transferred bypipette into the centre of each well of a number of 96-well, flatbottomed non-tissue-culture-treated microtitre plate (Bibby SterilinCatalogue No. 642000). The plates were placed briefly on ice to speedthe gelling of the agarose-cantaining droplets. Aliquots (90 μl) ofmedium which had been cooled to 4° C. were transferred into each well,taking care not to disturb the microdroplets. Test compounds werediluted from a 10 mM stock solution in DMSO using RPMI medium asdescribed above. Aliquots (10 μl) of the diluted test compounds weretransferred to the wells, again taking care not to disturb themicrodroplets. The plates were incubated at 37° C. in a humidified (7.5%CO₂: 95% air) incubator for about 48 hours.

[0586] Migration was assessed visually and the distance of migration wasmeasured back to the edge of the agar droplet. A migratory inhibitoryIC₅₀ was derived by plotting the mean migration measurement against testcompound concentration.

[0587] (d) In Vivo A549 Xenograft Growth Assay

[0588] This test measures the ability of compounds to inhibit the growthof the A549 human carcinoma grown as a tumour in athymic nude mice(Alderley Park nu/nu strain). A total of about 5×10⁶ A549 cells inmatrigel (Beckton Dickinson Catalogue No. 40234) were injectedsubcutaneously into the left flank of each test mouse and the resultanttumours were allowed to grow for about 14 days. Tumour size was measuredtwice weekly using callipers and a theoretical volume was calculated.Animals were selected to provide control and treatment groups ofapproximately equal average tumour volume. Test compounds were preparedas a ball-milled suspension in 1% polysorbate vehicle and dosed orallyonce daily for a period of about 28 days. The effect on tumour growthwas assessed.

[0589] Although the pharmacological properties of the compounds of theFormula I vary with structural change as expected, in general activitypossessed by compounds of the Formula I, may be demonstrated at thefollowing concentrations or doses in one or more of the above tests (a),(b), (c) and (d): Test (a):- IC₅₀ in the range, for example, 0.001-10μM; Test (b):- IC₅₀ in the range, for example, 0.01-20 μM; Test (c):-activity in the range, for example, 0.01-25 μM; Test (d):- activity inthe range, for example, 1-200 mg/kg/day.

[0590] No physiologically-unacceptable toxicity was observed in Test (d)at the effective dose for compounds tested of the present invention.Accordingly no untoward toxicological effects are expected when acompound of Formula I, or a pharmaceutically-acceptable salt thereof, asdefined hereinbefore is administered at the dosage ranges definedhereinafter.

[0591] According to a further aspect of the invention there is provideda pharmaceutical composition which comprises a quinazoline derivative ofthe Formula I, or a pharmaceutically-acceptable thereof, as definedhereinbefore in association with a pharmaceutically-acceptable diluentor carrier.

[0592] The compositions of the invention may be in a form suitable fororal use (for example as tablets, lozenges, hard or soft capsules,aqueous or oily suspensions, emulsions, dispersible powders or granules,syrups or elixirs), for topical use (for example as creams, ointments,gels, or aqueous or oily solutions or suspensions), for administrationby inhalation (for example as a finely divided powder or a liquidaerosol), for administration by insufflation (for example as a finelydivided powder) or for parenteral administration (for example as asterile aqueous or oily solution for intravenous, subcutaneous,intramuscular or intramuscular dosing or as a suppository for rectaldosing).

[0593] The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

[0594] The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, forexample from 1 to 30 mg) compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition.

[0595] The size of the dose for therapeutic or prophylactic purposes ofa compound of the Formula I will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine.

[0596] In using a compound of the Formula I for therapeutic orprophylactic purposes it will generally be administered so that a dailydose in the range, for example, 0.1 mg/kg to 75 mg/kg body weight isreceived, given if required in divided doses. In general lower doseswill be administered when a parenteral route is employed. Thus, forexample, for intravenous administration, a dose in the range, forexample, 0.1 mg/kg to 30 mg/kg body weight will generally be used.Similarly, for administration by inhalation, a dose in the range, forexample, 0.05 mg/kg to 25 mg/kg body weight will be used. Oraladministration is however preferred, particularly in tablet form.Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of acompound of this invention.

[0597] According to a further aspect of the invention there is provideda quinazoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore foruse in a method of treatment of the human or animal body by therapy.

[0598] As stated above, it is known that the predominant role of c-Srcnon-receptor tyrosine kinase is to regulate cell motility which isnecessarily required for a localised tumour to progress through thestages of dissemination into the blood stream, invasion of other tissuesand initiation of metastatic tumour growth. We have found that thequinazoline derivatives of the present invention possess potentanti-tumour activity which it is believed is obtained by way ofinhibition of one or more of the non-receptor tyrosine-specific proteinkinases such as c-Src kinase that are involved in the signaltransduction steps which lead to the invasiveness and migratory abilityof metastasising tumour cells.

[0599] Accordingly the quinazoline derivatives of the present inventionare of value as anti-tumour agents, in particular as selectiveinhibitors of the motility, dissemination and invasiveness of mammaliancancer cells leading to inhibition of metastatic tumour growth.Particularly, the quinazoline derivatives of the present invention areof value as anti-invasive agents in the containment and/or treatment ofsolid tumour disease. Particularly, the compounds of the presentinvention are expected to be useful in the prevention or treatment ofthose tumours which are sensitive to inhibition of one or more of themultiple non-receptor tyrosine kinases such as c-Src kinase that areinvolved in the signal transduction steps which lead to the invasivenessand migratory ability of metastasising tumour cells. Further, thecompounds of the present invention are expected to be useful in theprevention or treatment of those tumours which are mediated alone or inpart by inhibition of the enzyme c-Src, ie. the compounds may be used toproduce a c-Src enzyme inhibitory effect in a warm-blooded animal inneed of such treatment. Specifically, the compounds of the presentinvention are expected to be useful in the prevention or treatment ofsolid tumour disease.

[0600] Thus according to this aspect of the invention there is providedthe use of a quinazoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore in themanufacture of a medicament for use as an anti-invasive agent in thecontainment and/or treatment of solid tumour disease.

[0601] According to a further feature of this aspect of the inventionthere is provided a method for producing an anti-invasive effect by thecontainment and/or treatment of solid tumour disease in a warm-bloodedanimal, such as man, in need of such treatment which comprisesadministering to said animal an effective amount of a quinazolinederivative of the Formula I, or a pharmaceutically-acceptable saltthereof, as defined hereinbefore.

[0602] According to a further aspect of the invention there is providedthe use of a quinazoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore in themanufacture of a medicament for use in the prevention or treatment ofsolid tumour disease in a warm-blooded animal such as man.

[0603] According to a further feature of this aspect of the inventionthere is provided a method for the prevention or treatment of solidtumour disease in a warm-blooded animal, such as man, in need of suchtreatment which comprises administering to said animal an effectiveamount of a quinazoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore.

[0604] According to a further aspect of the invention there is providedthe use of a quinazoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore in themanufacture of a medicament for use in the prevention or treatment ofthose tumours which are sensitive to inhibition of non-receptor tyrosinekinases such as c-Src kinase that are involved in the signaltransduction steps which lead to the invasiveness and migratory abilityof metastasising tumour cells.

[0605] According to a further feature of this aspect of the inventionthere is provided a method for the prevention or treatment of thosetumours which are sensitive to inhibition of non-receptor tyrosinekinases such as c-Src kinase that are involved in the signaltransduction steps which lead to the invasiveness and migratory abilityof metastasising tumour cells which comprises administering to saidanimal an effective amount of a quinazoline derivative of the Formula I,or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.

[0606] According to a further aspect of the invention there is providedthe use of a quinazoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore in themanufacture of a medicament for use in providing a c-Src kinaseinhibitory effect.

[0607] According to a further feature of this aspect of the inventionthere is provided a method for providing a c-Src kinase inhibitoryeffect which comprises administering to said animal an effective amountof a quinazoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore.

[0608] The anti-invasive treatment defined hereinbefore may be appliedas a sole therapy or may involve, in addition to the quinazolinederivative of the invention, conventional surgery or radiotherapy orchemotherapy. Such chemotherapy may include one or more of the followingcategories of anti-tumour agents:

[0609] (i) other anti-invasion agents (for example metalIoproteinaseinhibitors like marimastat and inhibitors of urokinase plasminogenactivator receptor function);

[0610] (ii) antiproliferative/antineoplastic drugs and combinationsthereof, as used in medical oncology, such as alkylating agents (forexample cis-platin, carboplatin, cyclophosphamide, nitrogen mustard,melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites(for example antifolates such as fluoropyrimidines like 5-fluorouraciland tegafur, raltitrexed, methotrexate, cytosine arabinoside andhydroxyurea, or, for example, one of the preferred antimetabolitesdisclosed in European Patent Application No. 562734 such as(2S)-2-{o-fluoro-p-[N-{2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzamido}-4-(tetrazol-5-yl)butyricacid); antitumour antibiotics (for example anthracyclines likeadriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin,mitomycin-C, dactinomycin and mithramycin); antimitotic agents (forexample vinca alkaloids like vincristine, vinblastine, vindesine andvinorelbine and taxoids like taxol and taxotere); and topoisomeraseinhibitors (for example epipodophyllotoxins like etoposide andteniposide, amsacrine, topotecan and camptothecin);

[0611] (iii) cytostatic agents such as antioestrogens (for exampletanioxifen, toremifene, raloxifene, droloxifene and iodoxyfene),antiandrogens (for example bicalutamide, flutamide, nilutamide andcyproterone acetate), LHRH antagonists or LHRH agonists (for examplegoserelin, leuprorelin and buserelin), progestogens (for examplemegestrol acetate), aromatase inhibitors (for example as anastrozole,letrazole, vorazole and exemestane) and inhibitors of 5α-reductase suchas finasteride;

[0612] (iv) inhibitors of growth factor function, for example suchinhibitors include growth factor antibodies, growth factor receptorantibodies, tyrosine kinase inhibitors and serine/threonine kinaseinhibitors, for example inhibitors of the epidermal growth factor family(for example the EGFR tyrosine kinase inhibitorsN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(CP 358774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine(CI 1033)), for example inhibitors of the platelet-derived growth factorfamily and for example inhibitors of the hepatocyte growth factorfamily; and

[0613] (v) antiangiogenic agents such as those which inhibit vascularendothelial growth factor such as the compounds disclosed inInternational Patent Applications WO 97/22596, WO 97/30035, WO 97/32856and WO 98/13354 and those that work by other mechanisms (for examplelinomide, inhibitors of integrin αvβ3 function and angiostatin).

[0614] Such conjoint treatment may be achieved by way of thesimultaneous, sequential or separate dosing of the individual componentsof the treatment. Such combination products employ the compounds of thisinvention within the dosage range described hereinbefore and the otherpharmaceutically-active agent within its approved dosage range.

[0615] According to this aspect of the invention there is provided apharmaceutical product comprising a quinazoline derivative of theformula I as defined hereinbefore and an additional anti-tumour agent asdefined hereinbefore for the conjoint treatment of cancer.

[0616] Although the compounds of the Formula I are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit the effects of c-Src.Thus, they are useful as pharmacological standards for use in thedevelopment of new biological tests and in the search for newpharmacological agents.

[0617] The invention will now be illustrated in the following Examplesin which, generally:

[0618] (i) operations were carried out at ambient temperature, i.e. inthe range 17 to 25° C. and under an atmosphere of an inert gas such asargon unless otherwise stated;

[0619] (ii) evaporations were carried out by rotary evaporation in vacuoand work-up procedures were carried out after removal of residual solidsby filtration;

[0620] (iii) column chromatography (by the flash procedure) and mediumpressure liquid chromatography (MPLC) were performed on Merck Kieselgelsilica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phasesilica obtained from E. Merck, Darmstadt, Germany or high pressureliquid chromatography (HPLC) was performed on C18 reverse phase silica,for example on a Dynamax C-18 60 Å preparative reversed-phase column;

[0621] (iv) yields, where present, are not necessarily the maximumattainable;

[0622] (v) in general, the end-products of the Formula I havesatisfactory microanalyses and their structures were confirmed bynuclear magnetic resonance (NMR) and/or mass spectral techniques;fast-atom bombardment (FAB) mass spectral data were obtained using aPlatform spectrometer and, where appropriate, either positive ion dataor negative ion data were collected; NMR chemical shift values weremeasured on the delta scale [proton magnetic resonance spectra weredetermined using a Jeol JNM EX 400 spectrometer operating at a fieldstrength of 400 MHz, Varian Gemini 2000 spectrometer operating at afield strength of 300 MHz or a Bruker AM300 spectrometer operating at afield strength of 300 MHz]; the following abbreviations have been used:s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad;

[0623] (vi) intermediates were not generally fully characterised andpurity was assessed by thin layer chromatographic, HPLC, infra-red (IR)and/or NMR analysis;

[0624] (vii) melting points are uncorrected and were determined using aMettler SP62 automatic melting point apparatus or an oil-bath apparatus;melting points for the end-products of the Formula I were determinedafter crystallisation from a conventional organic solvent such asethanol, methanol, acetone, ether or hexane, alone or in admixture;

[0625] (viii) the following abbreviations have been used:

[0626] DMF N,N-dimethylformamide

[0627] DMSO dimethylsulphoxide

[0628] THF tetrahydrofuran

[0629] DMA N,N-dimethylacetamide

EXAMPLE 14-(2-chloro-5-methoxyanilino)-5-(3-morpholinopropoxy)quinazoline

[0630] Di-tert-butyl azodicarboxylate (0.208 g) was added dropwise to astirred mixture of4-(2-chloro-5-methoxyanilino)-5-hydroxy-7-methoxyquinazoline (0.2 g),4-(3-hydroxypropyl)morpholine (Bull. Soc. Chim. Fr., 1962, 1117; 0.131g), triphenylphosphine (0.237 g) and methylene chloride (3 ml). Thereaction mixture was stirred at ambient temperature for 1 hour. Themixture was evaporated and the residue was purified by columnchromatography on silica using a 99:1 mixture of methylene chloride anda saturated methanolic ammonia solution as eluent. The material soobtained was triturated under diethyl ether. The resultant solid wasisolated, washed with diethyl ether and dried under vacuum to give thetitle compound (0.12 g); NMR Spectrum: (DMSOd₆ and CF₃COOD) 2.35 (m,2H), 3.1 (t, 2H), 3.3 (t, 2H), 3.5 (d, 2H), 3.68 (t, 2H), 3.8 (s, 3H),4.0 (d, 2H), 4.02 (s, 3H), 4.6 (t, 2H), 6.93 (s, 1H), 7.05-7.15 (m, 2H),7.5 (s, 1H), 7.57 (d, 1H), 8.87 (s, 1H); Mass Spectrum: M+H⁺ 459 and461; Elemental Analysis: Found C, 60.0; H, 6.0; N, 12.1; C₂₃H₂₇ClN₄O₄requires C, 60.19; H, 5.93; N, 12.2%.

[0631] The 4-(2-chloro-5-methoxyanilino)-5-hydroxy-7-methoxyquinazolineused as a starting material was prepared as follows:

[0632] A mixture of 3,5-dimethoxyaniline hydrochloride (54.7 g), oxalylchloride (54 ml) and methanol (500 ml) was stirred and heated to refluxfor 1.5 hours. The mixture was cooled to ambient temperature. Theprecipitate was isolated, washed in turn with methanol and diethyl etherand dried under vacuum to give 4,6-dimethoxy-2,3-dioxoindoline (55 g);NMR Spectrum: (DMSOd₆) 3.85 (s, 3H), 3.9 (s, 3H), 6.0 (s, 1H), 6.2 (s,1H), 10.9 (s, 1H); Mass Spectrum: M+Na⁺ 230.

[0633] Hydrogen peroxide (30% solution in water, 30 ml) was addeddropwise to a stirred solution of 4,6-dimethoxy-2,3-dioxoindoline (27 g)in a concentrated aqueous sodium hydroxide solution (33%, 220 ml). Theresultant mixture was stirred at ambient temperature for 10 minutes. Icewas added and the basicity of the mixture was reduced to pH9 by theaddition of concentrated aqueous hydrochloric acid and the mixture wasthen acidified to pH3.5 by the addition of glacial acetic acid. Theresultant precipitate was isolated, washed with water and driedovernight under vacuum to give 2-amino-4,6-dimethoxybenzoic acid (15.9g); NMR Spectrum: (DMSOd₆) 3.7 (s, 3H),3.78 (s, 3H), 5.79 (s, 1H), 5.92(s, 1H).

[0634] Using an analogous procedure to that described by Lombardi etal., Chemistry & Industry, 1990, 708, diazomethane was generated from amixture of N-methyl-N-nitroso-4-toluenesulphonamide (31 g), ethanol (200ml) and a saturated aqueous sodium hydroxide solution (35 ml) andbubbled though a solution of 2-amino-4,6-dimethoxybenzoic acid (15.9 g)in methylene chloride (280 ml) which had been cooled to 0° C. Theresultant reaction mixture was evaporated and the residue was purifiedby column chromatography on silica using methylene chloride as eluent.There was thus obtained methyl 2-amino-4,6-dimethoxybenzoate (16.2 g);NMR Spectrum: (DMSOd₆) 3.65 (s, 3H), 3.7 (s, 6H), 5.75 (s, 1H), 5.9 (s,1H), 6.2 (br s, 2H).

[0635] A mixture of methyl 2-amino-4,6-dimethoxybenzoate (16 g),formamidine acetate (24 g) and 2-methoxyethanol (330 ml) was stirred andheated to reflux until all of the starting material had reacted. Themixture was evaporated and the residue was triturated under water (100ml). The resultant solid was isolated, washed with water and dried undervacuum to give 5,7-dimethoxy-3,4-dihydroquinazolin-4-one (14.5 g); NMRSpectrum: (DMSOd₆) 3.82 (s, 3H), 3.86 (s, 3H), 6.5 (s, 1H), 6.7 (s, 1H),7.9 (s, 1H), 11.7 (br s, 1H).

[0636] A mixture of a portion (0.35 g) of the material so obtained,phosphoryl chloride (0.95 ml) and acetonitrile (8 ml) was stirred andheated to reflux for 2 hours. The mixture was cooled to 0°C. andisopropanol (8 ml) and 2-chloro-5-methoxyaniline (0.321 g) were added inturn. The resultant mixture was heated to reflux for 1.5 hours. Themixture was cooled to ambient temperature and the resultant precipitatewas filtered, washed with isopropanol and with diethyl ether and driedunder vacuum. There was thus obtained4-(2-chloro-5-methoxyanilino)-5,7-dimethoxyquinazoline hydrochloride(0.365 g); NMR Spectrum: (DMSOd₆) 3.8 (s, 3H), 4.0 (s, 3H), 4.2 (s, 3H),7.0 (m, 3H), 7.6 (d, 1H), 7.62 (s, 1H), 8.8 (s, 1H), 10.9 (s, 1H); MassSpectrum: M+H⁺ 346 and 348.

[0637] A mixture of4-(2-chloro-5-methoxyanilino)-5,7-dimethoxyquinazoline hydrochloride(2.5 g), pyridine hydrochloride (0.76 g) and pyridine (50 ml) wasstirred and heated to reflux for 9 hours. The mixture was cooled toambient temperature and evaporated. The residue was suspended in waterand the mixture was basified to pH10 by the addition of aqueous sodiumbicarbonate solution. The resultant solid precipitate was isolated,washed in turn with water, with methylene chloride and with diethylether and dried overnight under vacuum at 50° C. There was thus obtained4-(2-chloro-5-methoxyanilino)-5-hydroxy-7-methoxyquinazoline (2.1 g);NMR Spectrum: (DMSOd₆) 3.8 (s, 3H), 3.85 (s, 3H), 6.3-6.5 (m, 2H), 6.8(d, 1H), 7.4 (d, 1H), 8.1 (br s, 1H), 8.42 (br s, 1H).

EXAMPLE 2

[0638] Using an analogous procedure to that described in Example 1, theappropriate 5-hydroxyquinazoline was reacted with the appropriatealcohol to give the compounds described in Table I. TABLE I

No. & Note (R¹)_(m) Q¹ (R²)_(n) [1] 7-methoxy3-(4-methylpiperazin-1-yl)propyl 2-chloro-5-methoxy [2] 7-methoxy2-piperidinomethyl 2-chloro-5-methoxy [3] 7-methoxy3-pyrrolidin-1-ylpropyl 2-chloro-5-methoxy [4] 7-methoxy2-(1,2,4-triazol-1-yl)ethyl 2-chloro-5-methoxy [5] 7-benzyloxy3-morpholinopropyl 2-chloro-5-methoxy [6] 7-benzyloxy3-pyrrolidin-1-ylpropyl 2-chloro-5-methoxy [7] hydrogen3-morpholinopropyl 2-bromo-5-methoxy [8] hydrogen3-(1,1-dioxotetrahydro-4H-1,4- 2-bromo-5-methoxy thiazin-4-yl)propyl [9]hydrogen 2-(4-methylpiperiazin-1-yl)ethyl 2-bromo-5-methoxy [10]hydrogen 3-(4-methylpiperazin-1-yl)propyl 2-chloro-5-methoxy [11]hydrogen 2-imidazol-1-ylethyl 2-chloro-5-methoxy [12] 7-methoxyN-methylpiperidin-4-yl 2-chloro-5-methoxy [13] hydrogenN-methylpiperidin-4-yl 2-chloro-5-methoxy [14] hydrogenN-methylpiperidin-4-yl 2-bromo-5-methoxy [15] hydrogenN-methylpiperidin-4-yl 2,5-dichloro [16] hydrogenN-(tert-butoxycarbonyl)- 2-chloro-5-methoxy piperidin-4-ylmethyl [17]hydrogen N-(tert-butoxycarbonyl)- 2-bromo-5-methoxy piperidin-4-ylmethyl[18] 7-methoxy 2-methoxyethyl 2-chloro-5-methoxy [19] 7-methoxyN-methylpyrrolidin-3-yl 2-bromo-5-methoxy [20] 7-benzyloxy4-tetrahydropyranyl 2-chloro-5-methoxy [21] hydrogen 4-tetrahydropyranyl2-chloro-5-methoxy [22] 7-benzyloxy 3-tetrahydrofuranyl2-chloro-5-methoxy [23] 7-(3-morpholinopropoxy) 3-tetrahydrofuranyl2-chloro-5-methoxy [24] 7-[3-(4-methylpiperiazin- 3-tetrahydrofuranyl2-chloro-5-methoxy 1-yl)propoxy] [25] 7-benzyloxy isopropyl2-chloro-5-methoxy [26] 7-methoxy 4-tetrahydropyranyl 2-bromo-5-methoxy[27] 7-methoxy 3-pyrrolidin-1-ylpropyl 6-chloro- 2,3-methylenedioxy [28]7-methoxy 3-(4-methylpiperazin-1-ylpropyl) 6-chloro- 2,3-methylenedioxy

[0639] Notes

[0640] [1] The reaction product was triturated under a mixture ofisopropanol and diethyl ether and a 6M solution of hydrogen chloride inisopropanol was added. The resultant precipitate was isolated, washedwith diethyl ether and dried under vacuum to give the product as thedihydrochloride salt; NMR Spectrum: (DMSOd₆) 2.2-2.4 (m, 2H), 2.8 (br s,3H), 3.2-3.7 (m, 10H), 3.8 (s, 3H), 4.0 (s, 3H), 4.6 (m, 2H), 6.95-7.0(m, 2H), 7.08 (s, 1H), 7.55 (d, 1H), 7.6 (s, 1H), 8.8 (s, 1H), 10.6 (s,1H); Mass Spectrum: M+H⁺ 472 and 474.

[0641] The 1-(3-hydroxypropyl)-4-methylpiperazine used as a startingmaterial was prepared as follows:

[0642] A mixture of 3-bromopropanol (20 ml), N-methylpiperazine (29 ml),potassium carbonate (83 g) and ethanol (200 ml) was stirred and heatedto reflux for 20 hours. The mixture was cooled to ambient temperatureand filtered. The filtrate was evaporated and the residue was trituratedunder diethyl ether. The resultant mixture was filtered and the filtratewas evaporated. The residue was purified by distillation to give therequired starting material as an oil; NMR Spectrum: (CDCl₃) 1.72 (m,2H), 2.3 (s, 3H), 2.2-2.8 (m, 8H), 2.6 (t, 2H), 3.8 (t, 2H), 5.3 (br s,1H).

[0643] [2] The reaction product was dissolved in a mixture ofisopropanol and diethyl ether and a 6M solution of hydrogen chloride inisopropanol was added. The resultant precipitate was isolated, washedwith diethyl ether and dried under vacuum to give the product as thedihydrochloride'salt; NMR Spectrum: (DMSOd₆ and CF₃COOD) 1.3-1.5 (m,2H), 1.65-1.9 (m, 4H), 3.02 (t, 2H), 3.6 (d, 2H), 3.7 (br s, 2H), 3.8(s, 3H), 4.02 (s, 3H), 4.9 (br s, 2H), 7.0 (s, 1H), 7.05 (m, 1H), 7.1(s, 1H), 7.3 (s, 1H), 7.58 (d, 1H), 8.8 (s, 1H); Mass Spectrum: M+H⁺ 443and 445.

[0644] [3] The reaction product was dissolved in a mixture ofisopropanol and diethyl ether and a 6M solution of hydrogen chloride inisopropanol was added. The resultant precipitate was isolated, washedwith diethyl ether and dried under vacuum to give the product as thedihydrochloride salt; NMR Spectrum: (DMSOd₆ and CF₃COOD) 1.9 (m, 2H),2.05 (m, 2H), 2.35 (m, 2H), 3.02 (m, 2H), 3.35 (t, 2H), 3.6 (m, 2H), 3.8(s, 3H), 4.02 (s, 3H), 4.6 (t, 2H), 6.95 (d, 1H), 7.05 (m, 1H), 7.1 (s,1H), 7.5 (d, 1H), 7.6 (d, 1H), 8.9 (s, 1H); Mass Spectrum: M+H⁺ 443 and445.

[0645] The N-(3-hydroxypropyl)pyrrolidine used as a starting materialwas prepared as follows:

[0646] A mixture of 3-chloropropanol (66 g), pyrrolidine (50 g),potassium carbonate (145 g) and acetonitrile (1 L) was stirred andheated to reflux for 20 hours. The mixture was cooled to ambienttemperature and filtered. The filtrate was evaporated and the residuewas purified by distillation to give the required starting material asan oil (62 g); NMR Spectrum: (CDCl₃) 1.6-1.8 (m, 6H), 2.55 (br s, 4H),2.75 (t, 2H), 3.85 (t, 2H), 5.5 (br s, 1H).

[0647] [4] The product was precipitated from the reaction mixture by theaddition of further methylene chloride. The product was isolated, washedwith diethyl ether and dried under vacuum. The product so obtained gavethe following data: NMR Spectrum: (DMSOd₆ and CF₃COOD) 3.82 (s, 3H), 4.0(s, 3H), 4.8 (m, 2H), 4.85 (m, 2H), 6.9 (s, 1H), 7.05 (s, 1H), 7.1 (m,1H), 7.3 (d, 1H), 7.58 (d, 1H), 7.65 (s, 1H), 8.67 (s, 1H), 8.79 (s,1H); Mass Spectrum: M+H⁺ 427 and 429.

[0648] The N ¹-(2-hydroxyethyl)-1,2,4-triazole used as a startingmaterial was prepared according to the procedure disclosed in Ann.Pharm. Fr., 1977, 35, 503.

[0649] [5] The product gave the following data: NMR Spectrum: (DMSOd₆)2.1 (m, 2H), 2.32 (br s, 4H), 2.45 (t, 2H), 3.52 (m, 4H), 3.8 (s, 3H),4.5 (t, 2H), 5.3 (s, 2H), 6.8 (m, 1H), 6.95 (s, 1H), 6.92 (s, 1H),7.3-7.6 (m, 6H), 8.35 (s, 1H), 8.55 (s, 1H), 10.12 (s, 1H); MassSpectrum: M+H⁺ 535 and 537.

[0650] The7-benzyloxy-4-(2-chloro-5-methoxyanilino)-5-hydroxyquinazoline used as astarting material was prepared as follows:

[0651] A mixture of 3,5-dibenzyloxyaniline hydrochloride (J. Org. Chem.,1975, 40, 1556; 10 g) and oxalyl chloride (15 ml) was heated to 170° C.for 3 hours. The mixture was cooled to ambient temperature, methanol (45ml) was added and the mixture was heated to reflux for 1 hour. Themixture was cooled to ambient temperature and the precipitate wasisolated, washed with methanol and dried under vacuum to give4,6-dibenzyloxy-2,3-dioxoindoline (8.8 g); NMR Spectrum: (DMSOd₆) 5.22(s, 2H), 5.28 (s, 2H), 6.12 (s, 1H), 6.42 (s, 1H), 7.3-7.55 (m, 10H),10.97 (s, 1H).

[0652] Hydrogen peroxide (30% solution in water, 13 ml) was addeddropwise to a stirred solution of 4,6-dibenzyloxy-2,3-dioxoindoline(14.3 g) in a concentrated aqueous sodium hydroxide solution (22.3 g in90 ml of water) which had been heated to 70° C. The resultant mixturewas stirred at 70° C. for 30 minutes and then cooled to ambienttemperature. Ice was added and the basicity of the mixture was reducedto pH9 by the addition of 2N aqueous hydrochloric acid and the mixturewas then acidified to pH3.7 by the addition of glacial acetic acid. Theresultant precipitate was purified by column chromatography on silicausing a 99:1 mixture of methylene chloride and methanol as eluent. Therewas thus obtained 2-amino-4,6-dibenzyloxybenzoic acid (8 g); NMRSpectrum: (DMSOd₆) 5.05 (s, 2H), 5.15 (s, 2H), 6.01 (s, 1H), 6.05 (s,1H), 7.3-7.6 (m, 10H).

[0653] Using an analogous procedure to that described by Lombardi etal., Chemistry & Industry, 1990, 708, diazomethane was generated from amixture of N-methyl-N-nitroso-4-toluenesulphonamide (11.5 g), ethanol(60 ml) and a saturated aqueous sodium hydroxide solution (30 ml) andbubbled though a solution of 2-amino-4,6-dibenzyloxybenzoic acid (8 g)in methylene chloride (170 ml) which had been cooled to 0°C. Theresultant reaction mixture was evaporated and the residue was trituratedunder diethyl ether. There was thus obtained methyl2-amino-4,6-dibenzyloxybenzoate (7.7 g); NMR Spectrum: (DMSOd₆) 3.74 (s,3H), 5.07 (s, 2H), 5.11 (s, 2H), 6.0 (s, 1H), 6.04 (s, 1H), 6.25 (br s,2H), 7.28-7.5 (m, 10H).

[0654] A mixture of methyl 2-amino-4,6-dibenzyloxybenzoate (7.7 g),formamidine acetate (7.2 g) and 2-methoxyethanol (100 ml) was stirredand heated to reflux until all of the starting material had reacted. Themixture was evaporated and the residue was triturated under water (60ml). The resultant solid was isolated, washed with water and dried undervacuum to give 5,7-dibenzyloxy-3,4-dihydroquinazolin-4-one (6.8 g); NMRSpectrum: (DMSOd₆) 5.24 (s, 4H), 6.75 (s, 1H), 6.8 (s, 1H), 7.3-7.7 (m,10H), 7.95 (s, 1H), 11.75 (br s, 1H).

[0655] A mixture of a portion (6 g) of the material so obtained,phosphoryl chloride (1.72 ml), diisopropylethylamine (7.3 ml) and1,2-dichloroethane (60 ml) was stirred and heated to reflux for 2 hours.The mixture was evaporated and a mixture of the residue and isopropanol(80 ml) was cooled to 10° C. and 2-chloro-5-methoxyaniline (3.4 g) anddiisopropylethylamine (1.45 ml) were added in turn. The resultantmixture was heated to reflux for 1.5 hours. The mixture was cooled toambient temperature and the resultant precipitate was isolated, washedwith isopropanol and with diethyl ether and dried under vacuum. Therewas thus obtained4-(2-chloro-5-methoxyanilino)-5,7-dibenzyloxyquinazoline hydrochloride(6.35 g); NMR Spectrum: (DMSOd₆) 3.8 (s, 3H), 5.31 (s, 2H), 5.65 (s,2H), 6.95 (m, 1H), 7.02 (s, 1H), 7.15 (s, 1H), 7.3-7.5 (m, 9H), 7.6 (d,2H), 7.7 (s, 1H), 8.8 (s, 1H); Mass Spectrum: M+H⁺ 498 and 500.

[0656] A mixture of4-(2-chloro-5-methoxyanilino)-5,7-dibenzyloxyquinazoline hydrochloride(4.3 g), pyridine hydrochloride (0.94 g) and pyridine (90 ml) wasstirred and heated to reflux for 9 hours. The mixture was cooled toambient temperature and evaporated. The residue was triturated underwater. The resultant solid precipitate was isolated, washed with waterand dried overnight under vacuum. The material was then triturated undermethanol. The resultant solid was isolated and dried under vacuum. Therewas thus obtained7-benzyloxy4-(2-chloro-5-methoxyanilino)-5-hydroxyquinazoline (3.1 g);NMR Spectrum: (DMSOd₆ and CF₃COOD) 3.85 (s, 3H), 5.3 (s, 2H), 6.85 (s,2H), 7.0 (m, 1H), 7.3-7.6 (m, 6H),7.8 (d, 1H), 8.85 (s, 1H).

[0657] [6] The product gave the following data: NMR Spectrum: (CDCl₃)1.75 (br s, 4H), 2.2 (m, 2H), 2.5 (br s, 4H), 2.65 (t, 2H), 3.85 (s,3H), 4.4 (t, 2H), 5.2 (s, 2H), 6.62 (d, 1H), 6.7 (s, 1H), 6.95 (s, 1H),7.2-7.5 (m, 6H), 8.4 (s, 1H), 8.6 (s, 1H), 10.1 (s, 1H); Mass Spectrum:M+H⁺ 519.

[0658] [7] The reaction product was triturated under diethyl ether, a6.3M solution of hydrogen chloride in isopropanol was added and themixture was stirred at ambient temperature for 1 hour. The resultantprecipitate was isolated, washed with diethyl ether and dried undervacuum to give the product as a dihydrochloride salt which gave thefollowing data: NMR Spectrum: (DMSOd₆ and CF₃COOD) 2.3-2.45 (m, 2H), 3.1(t, 2H), 3.3 (t, 2H), 3.45 (d, 2H), 3.75 (t, 2H), 3.81 (s, 3H), 4.0 (d,2H), 4.68 (t, 2H), 7.08 (m, 1H), 7.5-7.7 (m, 4H), 8.1 (m, 1H), 8.95 (s,1H); Mass Spectrum: M+H⁺ 473 and 475.

[0659] The 4-(2-bromo-5-methoxyanilino)-5-hydroxyquinazoline used as astarting material was prepared as follows:

[0660] A mixture of 5-methoxy-3,4-dihydroquinazolin-4-one (InternationalPatent Application WO 96/09294, pages 28 and 29; 2.1 g), phosphorylchloride (1.23 ml), diisopropylethylamine (5.2 ml) and1,2-dichloroethane (20 ml) was stirred and heated to 80° C. for 3 hours.The mixture was evaporated. The residue was dissolved in isopropanol (20ml) and 2-bromo-5-methoxyaniline (J. Amer. Chem. Soc., 1994, 116, 11797;2.45 g) and a 6M solution of hydrogen chloride in isopropanol (0.33 ml)were added in turn. The resultant mixture was heated to 80° C. for 1.5hours. The mixture was cooled to ambient temperature and the resultantprecipitate was isolated, washed with isopropanol and with diethyl etherand dried under vacuum. There was thus obtained4-(2-bromo-5-methoxyanilino)-5-methoxyquinazoline hydrochloride (3.8 g);NMR Spectrum: (DMSOd₆ and CF₃COOD) 3.82 (s, 3H), 4.2 (s, 3H), 7.0 (m,1H), 7.48 (d, 1H), 7.5 (d, 1H), 7.55 (d, 1H), 7.75 (d, 1H), 8.1 (m, 1H),7.92 (s, 1H); Mass Spectrum: M+H⁺ 360 and 362.

[0661] A mixture of 4-(2-bromo-5-methoxyanilino)-5-methoxyquinazolinehydrochloride (3.5 g), pyridine hydrochloride (2 g) and pyridine (30 ml)was stirred and heated to reflux for 18 hours. The mixture was cooled toambient temperature and evaporated. The residue was suspended in water.the mixture was basified to pH11 by the addition of a concentratedammonium hydroxide solution and stirred for 1 hour. The resultantprecipitate was isolated, washed with water and with diethyl ether anddried under vacuum. There was thus obtained4-(2-bromo-5-methoxyanilino)-5-hydroxyquinazoline (2.15 g); NMRSpectrum: (DMSOd₆ and CF₃COOD) 3.8 (s, 3H), 6.95 (m, 1H), 7.25 (d, 1H),7.3 (d, 1H), 7.7 (s, 1H), 7.75 (d, 1H), 7.9 (m, 1H), 8.9 (s, 1H); MassSpectrum: M+H⁺ 346 and 348.

[0662] [8] Using a similar work-up to that described in Note [7] above,the product was obtained as a dihydrochloride salt which gave thefollowing data: NMR Spectrum: (DMSOd₆ and CF₃COOD) 2.4-2.5 (m, 2H), 3.5(m, 2H), 3.7 (br s, 4H), 3.72-3.9 (br s, 4H), 3.8 (s, 3H), 4.7 (t, 2H),7.0 (m, 1H), 7.4-7.6 (m, 3H), 7.75 (d, 1H), 8.1 (m, 1H), 9.02 (s, 1H);Mass Spectrum: M+H⁺ 521 and 523.

[0663] The 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propan-1-ol usedas a starting material was prepared as follows:

[0664] A mixture of 3-aminopropan-1-ol (0.650 ml) and divinyl sulphone(1 g) was heated to 110° C. for 45 minutes. The mixture was allowed tocool to ambient temperature and was purified by column chromatography onsilica using a 19:1 mixture of methylene chloride and methanol aseluent. There was thus obtained3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propan-1-ol (0.8 g); NMRSpectrum: (CDCl₃) 1.7-1.8 (m, 2H), 2.73 (t, 2H), 3.06 (br s, 8H), 3.25(s, 1H), 3.78 (t, 2H); Mass Spectrum: M+H⁺ 194.

[0665] [9] Using a similar work-up to that described in Note [7] above,the product was obtained as a dihydrochloride salt which gave thefollowing data: Mass Spectrum: M+H⁺ 472 and 474.

[0666] The 1-(2-hydroxyethyl)-4-methylpiperazine used as a startingmaterial was prepared as follows:

[0667] A mixture of 2-bromoethanol (2.36 g), N-methylpiperazine (1.26g), potassium carbonate (5.0 g) and ethanol (150 ml) was stirred andheated to reflux for 18 hours. The mixture was cooled to ambienttemperature and filtered. The filtrate was evaporated and the residuewas triturated under a mixture of methylene chloride and acetone. Theresultant mixture was filtered and the filtrate was evaporated to givethe required starting material as an oil (0.87 g); NMR Spectrum: (CDCl₃)2.18 (s, 3H), 2.3-2.7 (br m, 8H), 2.56 (t, 2H), 3.61 (t, 2H).

[0668] [10] Using a similar work-up to that described in Note [7] above,the product was obtained as a dihydrochloride salt which gave thefollowing data: NMR Spectrum: (DMSOd₆ and CF₃COOD) 2.35-2.45 (m, 2H),2.9 (s, 3H), 3.2-3.9 (m, 10H), 3.85 (s, 3H), 4.7 (t, 2H), 7.05 (m, 1H),7.45-7.6 (m, 4H), 8.1 (m, 1H), 8.95 (s, 1H); Mass Spectrum: M+H⁺ 442 and444.

[0669] [11] Using a similar work-up to that described in Note [7] above,the product was obtained as a dihydrochloride salt which gave thefollowing data: NMR Spectrum: (DMSOd₆ and CF₃COOD) 3.82 (s, 3H), 4.85(t, 2H), 5.05 (t, 2H), 7.05 (m, 1H), 7.35 (d, 1H), 7.5-7.65 (m, 3H), 7.7(s, 1H), 7.8 (s, 1H), 8.1 (m, 1H), 8.95 (s, 1H), 9.15 (s, 1H); MassSpectrum: M+H⁺ 396 and 398.

[0670] The N-(2-hydroxyethyl)imidazole used as a starting material wasprepared according to the procedure disclosed in J. Med. Chem., 1993,25, 4052.

[0671] [12] The 4-hydroxy-1-methylpiperidine was added after the otherreaction components had been stirred together at 0° C. for 1 hour. Theresultant reaction mixture was stirred at ambient temperature for 3hours. The reaction mixture was filtered and the filtrate was washedwith a 1N aqueous sodium hydroxide solution. The organic solution wasevaporated and the residue was purified by column chromatography onsilica using a 98:2 mixture of methylene chloride and methanol aseluent. The material so obtained was triturated under a 6M solution ofhydrogen chloride in diethyl ether. The resultant solid was isolated,washed with diethyl ether and dried under vacuum to give the product asa dihydrochloride salt which gave the following data: NMR Spectrum:(DMSOd₆ and CF₃COOD) 2.0-2.15 (m, 2H), 2.15-2.3 (m, 4H), 2.35 (s, 3H),2.8-2.9 (m, 2H), 3.85 (s, 3H), 3.95 (s, 3H), 4.55 (m, 1H), 6.55 (s, 1H),6.65 (m, 1H), 6.85 (s, 1H), 7.3 (d, 1H), 8.15 (d, 1H), 8.55 (s, 1H),9.85 (br s, 1H); Mass Spectrum: M+H⁺ 429 and 431.

[0672] [13] Using a similar work-up to that described in Note [7] above,the product was obtained as a dihydrochloride salt which gave thefollowing data: NMR Spectrum: (DMSOd₆ and CF₃COOD) (two conformationalisomers were noted in a ratio of about 3:2) 2.2-2.4 (m, 2H), 2.5 (d,2H), 2.85 (s, 3H), 3.1-3.3 (m, 2H), 3.4-3.5 (m, 0.5H minor conformer),3.55-3.7 (d, 1H major conformer and 0.51H minor conformer), 2.8 (s, 3H),5.1-5.2 (m, 1H major conformer), 5.2-5.3 (m, 1H minor conformer), 7.05(m, 1H major conformer), 7.1 (m, 1H minor conformer), 7.4-7.8 (m, 4H),8.05-8.15 (m, 1H), 8.95 (s, 1H minor conformer), 9.0 (s, 1H majorconformer); Mass Spectrum: M+H⁺ 399 and 401.

[0673] [14] Using a similar work-up to that described in Note [7] above,the product was obtained as a dihydrochloride salt which gave thefollowing data: NMR Spectrum: (DMSOd₆ and CF₃COOD) (two conformationalisomers were noted in a ratio of about 3:2) 2.2-2.4 (m, 2H), 2.4-2.65(m, 2H), 2.8 (s, 3H major conformer), 2.82 (s, 3H minor conformer),3.1-3.3 (m, 2H), 3.45 (m, 0.5H minor conformer), 3.5-3.7 (m, 0.5H minorconformer), 3.8 (s, 3H), 5.1-5.2 (m, 1H major conformer), 5.25 (br s, 1Hminor conformer), 7.0 (m, 1H major conformer), 7.05 (m, 1H minorconformer), 7.4-7.8 (m, 4H), 8.12 (m, 1H), 8.9 (s, 1H minor conformer),9.0 (s, 1H); Mass Spectrum: M+H⁺ 443 and 445.

[0674] [15] Using a similar work-up to that described in Note [7] above,the product was obtained as a dihydrochloride salt which gave thefollowing data: NMR Spectrum: (DMSOd₆ and CF₃COOD) (two conformationalisomers were noted in a ratio of about 3:2) 2.15-2.3 (m, 2H), 2.4-2.52(m, 2H), 2.85 (s, 3H), 3.1-3.3 (m, 2H), 3.4-3.5 (m, 0.5H minorconformer), 3.6-3.7 (m, 1H minor conformer, 0.5H minor conformer),5.1-5.2 (m, 1H), 5.2-5.3 (m, 1H minor conformer), 7.5-7.6 (m, 2H),7.6-7.8 (m, 2H), 8.0-8.25 (m, 2H), 9.0 (s, 1H minor conformer), 9.1 (s,1H major conformer); Mass Spectrum: M+H⁺ 402 and 404.

[0675] The 4-(2,5-dichloroanilino)-5-hydroxyquinazoline used as astarting material was prepared as follows:

[0676] A mixture of 5-methoxy-3,4-dihydroquinazolin-4-one (1.8 g),phosphoryl chloride (1.03 ml), diisopropylethylamine (4.4 ml) and1,2-dichloroethane (20 ml) was stirred and heated to 80° C. for 3 hours.The mixture was evaporated. The residue was dissolved in isopropanol (20ml) and 2,5-dichloroaniline (1.95 g) and a 6M solution of hydrogenchloride in isopropanol (0.33 ml) were added in turn. The resultantmixture was heated to 80° C. for 1.5 hours. The mixture was cooled toambient temperature and the resultant precipitate was isolated, washedwith isopropanol and with diethyl ether and dried under vacuum. Therewas thus obtained 4-(2,5-dichloroanilino)-5-methoxyquinazolinehydrochloride (3.2 g); NMR Spectrum: (DMSOd₆) 4.19 (s, 3H), 7.45 (d,1H), 7.5-7.6 (m, 2H), 7.75 (d, 1H), 8.05-8.15 (m, 2H), 8.95 (s, 1H).

[0677] A mixture of 4-(2,5-dichloroanilino)-5-methoxyquinazolinehydrochloride (3.2 g), pyridine hydrochloride (2.1 g) and pyridine (30ml) was stirred and heated to reflux for 18 hours. The mixture wascooled to ambient temperature and evaporated. The residue was suspendedin water. the mixture was basified to pH11 by the addition of aconcentrated ammonium hydroxide solution and stirred for 1 hour. Theresultant precipitate was isolated, washed with water and with diethylether and dried under vacuum. There was thus obtained4-(2,5-dichloroanilino)-5-hydroxyquinazoline (1.3 g); NMR Spectrum:(DMSOd₆ and CF₃COOD) 7.25 (d, 1H), 7.3 (d, 1H), 7.5 (m, 1H), 7.7 (d,1H), 7.95 (m, 1H), 8.3 (s, 1H), 9.0 (s, 1H); Mass Spectrum: M+H⁺ 306 and308.

[0678] [16] The product gave the following data: NMR Spectrum: (CDCl₃)1.2-1.4 (m, 2H), 1.5 (s, 9H), 1.9 (d, 2H), 2.3 (m, 1H), 2.8 (t, 2H), 3.9(s, 3H), 4.1-4.2 (m, 2H), 4.2 (d, 2H), 6.66 (m, 1H), 6.93 (d, 1H), 7.7(m, 1H), 8.45 (d, 1H), 8.7 (s, 1H); Mass Spectrum: M+H⁺ 499 and 501.

[0679] The 4-(2-chloro-5-methoxyanilino)-5-hydroxyquinazoline used as astarting material was prepared as follows:

[0680] A mixture of 5-methoxy-3,4-dihydroquinazolin-4-one (2.1 g),phosphoryl chloride (1.23 ml), diisopropylethylamine (5.2 ml) and1,2-dichloroethane (20 ml) was stirred and heated to 80° C. for 3 hours.The mixture was evaporated. The residue was dissolved in isopropanol (20ml) and 2-chloro-5-methoxyaniline (1.9 g) and a 6M solution of hydrogenchloride in isopropanol (0.33 ml) were added in turn. The resultantmixture was heated to 80° C. for 1.5 hours. The mixture was cooled toambient temperature and the resultant precipitate was isolated, washedwith isopropanol and with diethyl ether and dried under vacuum. Therewas thus obtained 4-(2-chloro-5-methoxyanilino)-5-methoxyquinazolinehydrochloride (3.4 g); NMR Spectrum: (DMSOd₆) 3.8 (s, 3H), 4.17 (s, 3H),7.02 (m, 1H), 7.43 (d, 1H), 7.6 (m, 3H), 8.07 (m, 1H), 8.9 (s, 1H).

[0681] A mixture of the material so obtained, pyridine hydrochloride(1.1 g) and pyridine (30 ml) was stirred and heated to reflux for 18hours. The mixture was cooled to ambient temperature and evaporated. Theresidue was suspended in water, the mixture was basified to pH11 by theaddition of a concentrated ammonium hydroxide solution and stirred for 1hour. The resultant precipitate was isolated, washed with water and withdiethyl ether and dried under vacuum. There was thus obtained4-(2-chloro-5-methoxyanilino)-5-hydroxyquinazoline (1.4 g); NMRSpectrum: (DMSOd₆ and CF₃COOD) 3.83 (s, 3H), 7.01 (m, 1H), 7.25 (d, 1H),7.3 (d, 1H), 7.6 (d, 1H), 7.82 (d, 1H), 7.92 (m, 1H), 8.95 (s, 1H); MassSpectrum: M+H⁺ 302 and 304.

[0682] The N-(tert-butoxycarbonyl)piperidin-4-ylmethanol used as astarting material was prepared as follows:

[0683] A solution of di-tert-butyl dicarbonate (41.7 g) in ethyl acetate(75 ml) was added dropwise to a stirred solution of ethylpiperidine-4-carboxylate (30 g) in ethyl acetate (150 ml) which had beencooled to 0 to 5° C. in an ice-bath. The resultant mixture was stirredat ambient temperature for 48 hours. The mixture was poured into water(300 ml). The organic layer was separated, washed in turn with water(200 ml), 0.1N aqueous hydrochloric acid solution (200 ml), a saturatedaqueous sodium bicarbonate solution (200 ml) and brine (200 ml), driedover magnesium sulphate and evaporated. There was thus obtained ethylN-(tert-butoxycarbonyl)piperidine-4-carboxylate (48 g); NMR Spectrum:(CDCl₃) 1.25 (t, 3H), 1.45 (s, 9H), 1.55-1.7 (m, 2H), 1.8-2.0 (d, 2H),2.35-2.5 (m, 1H), 2.7-2.95 (t, 2H), 3.9-4.1 (br s, 2H), 4.15 (q, 2H).

[0684] A solution of the material so obtained in THF (180 ml) was cooledat 0° C. and lithium aluminium hydride (1M solution in THF; 133 ml) wasadded dropwise. The mixture was stirred at 0° C. for 2 hours. Water (30ml) and 2N aqueous sodium hydroxide solution (10 ml) were added in turnand the mixture was stirred for 15 minutes. The resultant mixture wasfiltered through diatomaceous earth and the solids were washed withethyl acetate. The filtrate was washed in turn with water and withbrine, dried over magnesium sulphate and evaporated. There was thusobtained N-(tert-butoxycarbonyl)piperidin-4-ylmethanol (36.3 g); NMRSpectrum: (CDCl₃) 1.05-1.2 (m, 2H), 1.35-1.55 (m, 10H), 1.6-1.8 (m, 2H),2.6-2.8 (t, 2H), 3.4-3.6 (t, 2H), 4.0-4.2 (br s, 2H).

[0685] [17] The product gave the following data: NMR Spectrum: (CDCl₃)1.2-1.35 (m, 2H), 1.5 (s, 9H), 1.9 (d, 2H), 2.35 (m, 1H), 2.75 (t, 2H),3.85 (s, 3H), 4.05-4.2 (m, 2H), 4.2 (d, 2H), 6.62 (m, 1H), 6.95 (d, 1H),7.7 (m, 1H), 8.25 (d, 1H), 8.7 (s, 1H); Mass Spectrum: M+H⁺ 543 and 545.

[0686] The 4-(2-bromo-5-methoxyanilino)-5-hydroxyquinazoline used as astarting material was prepared from5-methoxy-3,4-dihydroquinazolin-4-one using analogous procedures tothose described in the portion of Note [16] immediately above exceptthat 2-bromo-5-methoxyaniline was used in place of2-chloro-5-methoxyaniline.

[0687] [18] The product gave the following data: NMR Spectrum: (DMSOd₆)3.25 (s, 3H), 3.79 (s, 3H), 3.83 (m, 2H), 3.98 (s, 3H), 4.58 (m, 2H),6.95 (s, 1H), 7.0 (m, 1H), 7.07 (s, 1H), 7.55 (m, 2H), 8.8 (s, 1H),10.64 (s, 1H); Mass Spectrum: M+H⁺ 390 and 392.

[0688] [19] The reaction product was triturated under a mixture ofisopropanol and diethyl ether and a 6M solution of hydrogen chloride inisopropanol was added. The resultant precipitate was isolated, washedwith diethyl ether and dried under vacuum to give the product as thedihydrochloride salt; NMR Spectrum: (CDCl₃) 2.2-2.3 (m, 1H), 2.4 (s,3H), 2.4-2.5 (m, 1H), 2.5-2.6 (m, 1H), 2.8-2.9 (m, 1H), 2.95-3.1 (m,2H), 3.85 (s, 3H), 3.95 (s, 3H), 5.05 (m, 1H), 6.42 (s, 1H), 6.65 (m,1H), 6.88 (s, 1H), 7.5 (d, 1H), 7.9 (d, 1H), 8.55 (s, 1H), 9.7 (s, 1H);Mass Spectrum: M+H⁺ 459 and 461.

[0689] The 4-(2-bromo-5-methoxyanilino)-5-hydroxy-7-methoxyquinazolineused as a starting material was prepared as follows:

[0690] Using analogous procedures to those described in the second lastparagraph of the portion of Example 1 that is concerned with thepreparation of starting materials,5,7-dimethoxy-3,4-dihydroquinazolin-4-one (3 g) was reacted withphosphoryl chloride (1.5 ml) and the resultant product was reacted with2-bromo-5-methoxyaniline (3.53 g). There was thus obtained4-(2-bromo-5-methoxyanilino)-5,7-dimethoxyquinazoline hydrochloride (5g); NMR Spectrum: (DMSOd₆) 3.8 (s, 3H), 4.0 (s, 3H), 4.18 (s, 3H), 6.95(m, 3H), 7.6 (br s, 1H), 7.7 (d, 1H), 7.8 (s, 1H), 10.85 (s, 1H); MassSpectrum: M+H⁺ 391 and 393.

[0691] A mixture of the material so obtained, pyridine hydrochloride(1.4 g) and pyridine (100 ml) was stirred and heated to reflux for 6hours. A second portion (2.8 g) of pyridine hydrochloride was addedportionwise and the mixture was heated to reflux for a further 18 hours.The mixture was cooled to ambient temperature and evaporated. Thematerial so obtained was triturated under water. The precipitate wasisolated and washed with methylene chloride (100 ml) for 1 hour. Thesolid was isolated and dried under vacuum. There was thus obtained4-(2-bromo-5-methoxyanilino)-5-hydroxy-7-methoxyquinazoline (39 g); NMRSpectrum: (DMSOd₆ and CF₃COOD) 3.75 (s, 3H), 3.9 (s, 3H), 6.75 (s, 2H),6.92 (m, 1H), 7.58-7.7 (m, 2H), 8.8 (s, 1H).

[0692] [20] 4-Hydroxytetrahydropyran was used as the appropriatealcohol. The product gave the following data: NMR Spectrum: (DMSOd₆)1.75-1.9 (m, 2H), 2.15 (d, 2H), 3.5 (t, 2H), 3.8 (s, 3H), 3.9 (m, 2H),5.05 (m, 1H), 5.3 (s, 2H), 5.8 (m, 1H), 6.95 (d, 1H), 7.05 (d, 1H),7.3-7.6 (m, 6H), 8.1 (d, 1H), 8.5 (s, 1H), 9.85 (s, 1H); Mass Spectrum:M+H⁺ 492 and 494.

[0693] [21] The reaction product was dissolved in diethyl ether and a 6Msolution of hydrogen chloride in diethyl ether (0.1 ml) was added. Theresultant precipitate was isolated, washed with diethyl ether and driedunder vacuum to give the product as a hydrochloride salt which gave thefollowing data: NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 1.9-2.05 (m, 2H),2.18 (d, 2H), 3.55 (t, 2H), 3.82 (s, 3H), 3.95 (m, 2H), 5.15 (m, 1H),7.05 (m, 1H), 7.5 (d, 1H), 7.58 (d, 2H), 7.65 (d, 1H), 8.05 (m, 1H),8.95 (s, 1H); Mass Spectrum: M+H⁺ 386 hand 388.

[0694] [22] The product gave the following data: NMR Spectrum: (DMSOd₆and CF₃CO₂D) 2.2-2.3 (m, 1H), 2.35-2.5 (m, 1H), 3.8 (s, 3H), 3.8-3.9 (m,1H), 3.9-4.0 (m, 2H), 4.2 (d, 1H), 5.4 (s, 2H), 5.6 (br s, 1H), 7.01 (d,1H), 7.05 (s, 1H), 7.18 (s, 1H), 7.42 (d, 1H), 7.45 (m, 2H), 7.52 (s,1H), 7.55 (d, 2H), 7.6 (d, 1H), 8.9 (s, 1H); Mass Spectrum: M+H⁺ 477 and479.

[0695] [23] The product gave the following data: NMR Spectrum: (DMSOd₆)1.9-2.0 (m, 2H), 2.15-2.25 (m, 1H), 2.3-2.5 (m, 5H), 2.5 (t, 2H), 3.6(t, 4H), 3.8 (s, 3H), 3.9-4.0 (m, 3H), 4.1 (d, 1H), 4.2 (t, 2H), 5.45(t, 1H), 6.75-6.8 (m, 2H), 6.85 (s, 1H), 7.45 (d, 1H), 8.1 (s, 1H), 8.5(s, 1H), 9.72 (s, 1H); Mass Spectrum: M+H⁺ 515 and 517.

[0696] [24] The product gave the following data: NMR Spectrum: (DMSOd₆)1.9-2.0 (m, 2H), 2.14 (s, 3H), 2.15-2.35 (m, 2H), 2.2-2.6 (m, 10H), 3.8(s, 3H), 3.85-4.0 (m, 3H), 4.12 (d, 1H), 4.2 (t, 2H), 5.45 (t, 1H),7.75-7.8 (m, 2H), 7.85 (s, 1H), 7.45 (d, 1H), 8.1 (s, 1H), 8.5 (s, 1H),9.72 (s, 1H); Mass Spectrum: M+H⁺ 528 and 530.

[0697] [25] The product gave the following data: NMR Spectrum: (DMSOd₆and CF₃CO₂D) 1.5 (d, 6H), 3.82 (s, 3H), 5.2 (m, 1H), 5.4 (s, 2H), 6.98(s, 1H, 7.0 (m, 1H), 7.18 (s, 1H), 7.4 (d, 1H), 7.45 (m, 2H), 7.5-7.6(m, 2H), 7.65 (d, 1H), 8.9 (s, 1H); Mass Spectrum: M+H⁺ 449 and 451.

[0698] [26] The reaction product was dissolved in methylene chloride (2ml) containing methanol (a few drops) and a 6M hydrogen chloridesolution in diethyl ether (2 equivalents) was added. Diethyl ether (50ml) was added and the resultant precipitate was isolated, washed withdiethyl ether and dried under vacuum to give the product as adihydrochloride salt (0.135 g); NMR Spectrum: (DMSOd₆ and CF₃CO₂D)1.9-2.1. (m, 2H), 2.1-2.2 (m, 2H), 3.55 (m, 2H), 3.79 (s, 3H), 3.92 (m,2H), 4.0 (s, 3H), 5.15 (m, 1H), 6.9 (s, 1H), 6.95 (m, 1H), 7.15 (d, 1H),7.45 (d, 1H), 7.7 (d, 1H), 8.85 (s, 1H); Mass Spectrum: M+H⁺ 460 and462.

[0699] [27] The reaction product was triturated under a mixture of a 5Msolution of hydrogen chloride in isopropanol was added. The resultantprecipitate was isolated, washed with diethyl ether and dried undervacuum to give the product as the dihydrochloride salt; NMR Spectrum:(DMSOd₆ and CF₃CO₂D) 1.9 (m, 2H), 2.05 (m, 2H), 2.35 (m, 2H), 3.05 (m,2H), 3.3 (m, 2H), 3.6 (m, 2H), 4.05 (s, 3H), 4.65 (t, 2H), 6.15 (s, 2H),6.95 (d, 1H), 7.1 (m, 2H), 7.15 (d, 1H), 8.85 (s, 1H); Mass Spectrum:M+H⁺ 457 and 459.

[0700] The4-(6-chloro-2,3-methylenedioxyanilino)-5-hydroxy-7-methoxyquinazolineused as a starting, material was prepared as follows:

[0701] Phosphoryl chloride (2.7 ml) was added dropwise to a mixture of5,7-dimethoxy-3,4-dihydroquinazolin-4-one (1 g), diisopropylethylamine(2.27 ml) and 1,2-dichloroethane (20 ml) and the resultant mixture wasstirred and heated to 80° C. for 3 hours. The mixture was evaporated.There was thus obtained 4-chloro-5,7-dimethoxyquinazoline which was usedwithout further purification. The material so obtained was suspended inisopropanol (14 ml) and 6-chloro-2,3-methylenedioxyaniline (Example 17,Note [30]; 0.915 g) and a 5N solution of hydrogen chloride inisopropanol (0.97 ml) were added in turn. The reaction mixture wasstirred and heated to 90° C. for 1.5 hours. The mixture was cooled toambient temperature and the precipitate was isolated, washed withisopropanol and with diethyl ether and dried under vacuum. The materialso obtained was dissolved in a mixture of methylene chloride andmethanol and a saturated methanolic ammonia solution was added. Theresultant mixture was filtered and the filtrate was evaporated. Therewas thus obtained4-(6-chloro-2,3-methylenedioxyanilino)-5,7-dimethoxyquinazoline (1.36g); NMR Spectrum: (DMSOd₆) 3.95 (s, 3H), 4.1 (s, 3H), 6.1 (s, 2H), 6.85(d, 1H), 6.9 (d, 1H), 7.05 (d, 1H), 7.1 (d, 1H), 8.65 (s, 1H).

[0702] Pyridine (0.54 ml) was dissolved in methylene chloride (5 ml) anda 5N solution of hydrogen chloride in isopropanol (1.34 ml) was added.After a few minutes the mixture was evaporated. Pyridine (24 ml) wasadded followed by4-(6-chloro-2,3-methylenedioxyanilino)-5,7-dimethoxyquinazoline (1.2 g)and the reaction mixture was heated to 125° C. for 6 hours. Theresultant mixture was evaporated and the residue was triturated underwater. The resultant solid was isolated, washed with water and driedunder vacuum. The material so obtained was purified by columnchromatography on silica using a 7:3 mixture of methylene chloride andacetonitrile as eluent. There was thus obtained4-(6-chloro-2,3-methylenedioxyanlino)-5-hydroxy-7-methoxyquinazoline(0.72 g); NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 3.9 (s, 3H), 6.15 (s, 2H),6.75 (m, 2H), 7.05 (d, 1H), 7.1 (d, 1H), 8.75 (s, 1H).

[0703] [28] The reaction product was triturated under a mixture of a 5Msolution of hydrogen chloride in isopropanol was added. The resultantprecipitate was isolated, washed with diethyl ether and dried undervacuum to give the product as the dihydrochloride salt; NMR Spectrum:(DMSOd₆ and CF₃CO₂D) 2.35 (m, 2H), 2.9 (s, 3H), 3.2-4.0 (m, 10H), 4.05(s, 3H), 4.65 (t, 2H), 6.15 (s, 2H), 6.95 (d, 1H), 7.1 (m, 3H), 8.85 (s,1H); Mass Spectrum: M+H^(⇄) 486 and 488.

EXAMPLE 34-(2-bromo-5-methoxyanilino)-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline

[0704] A mixture of4-chloro-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline (0.11 g),2-bromo-5-methoxyaniline hydrochloride (0.099 g) and isopropanol (8 ml)was stirred and heated to 80° C. for 30 minutes. The mixture wasevaporated and the residue was triturated under the minimum volume ofisopropanol. The resultant solid was isolated, washed with isopropanoland with diethyl ether and dried under vacuum. There was thus obtainedthe title compound as a dihydrochloride salt (0.06 g). A sample of thematerial was treated with a saturated methanolic ammonia solution. Themixture was filtered and the filtrate was evaporated to give the titlecompound in free base form; NMR Spectrum (CDCl₃): 2.15-2.25 (m, 6H),2.35 (s, 3H), 2.9 (m, 2H), 3.84 (s, 3H), 3.93 (s, 3H), 4.6 (br s, 1H),6.62 (s, 1H), 6.6 (m, 1H), 6.85 (s, 1H), 7.5 (d, 1H), 7.9 (s, 1H), 8.55(s, 1H), 9.64 (br s, 1H); Mass Spectrum: M+H⁺ 473 and 475.

[0705] The 4-chloro-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazolineused as a starting material was prepared as follows:

[0706] Pyridine (40 ml) was added dropwise to magnesium bromide (3.6 g)which had been cooled to 0°C. 5,7-Dimethoxy-3,4-dihydroquinazolin-4-one(4 g) was added and the mixture was heated to reflux for 15 minutes. Themixture was evaporated and the residue was stirred under a mixture ofglacial acetic acid (12 ml) and water (80 ml) for 10 minutes Theresultant solid was isolated, washed with water and dried under vacuumat 50° C. There was thus obtained5-hydroxy-7-methoxy-3,4-dihydroquinazolin-4-one (3.75 g); NMRSpectrum:(DMSOd₆) 3.95 (s, 3H), 6.45 (s, 1H), 6.62 (s, 1H), 8.1 (s, 1H).

[0707] A portion (1.8 g) of the material so obtained was added to astirred suspension of sodium hydride (0.79 g of a 60% dispersion inmineral oil which was washed with THF) in DMF (18 ml). The mixture wasstirred at ambient temperature for I hour. The mixture was cooled to 0°C. and chloromethyl pivalate (1.62 ml) was added dropwise. The mixturewas stirred at ambient temperature for 1 hour, poured into a mixture ofglacial acetic acid (50 ml) and water (200 ml) and stirred at ambienttemperature for 5 minutes. The resultant precipitate was isolated,washed with water and dried overnight under vacuum. The solid wastriturated under pentane, isolated and dried under vacuum. There wasthus obtained5-hydroxy-7-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (2.5g); NMR Spectrum: (CDCl₃) 1.2 (s, 9H), 3.9 (s, 3H), 5.88 (s, 2H), 6.5(s, 1H), 6.68 (s, 1H), 8.15 (s, 1H), 11.36 (s, 1H).

[0708] A solution of di-tert-butyl azodicarboxylate (1.7 g) in methylenechloride (5 ml) was added to a stirred mixture of5-hydroxy-7-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (1.5g), triphenylphosphine (1.9 g), 4-hydroxy-1-methylpiperidine (0.675 g)and methylene chloride (20 ml) which had been cooled to 5° C. Themixture was stirred at ambient temperature for 1 hour. The mixture wasevaporated and the residue was purified by column chromatography onsilica using a 9:10:1 mixture of methylene chloride, ethyl acetate and asaturated methanolic ammonia solution as eluent. The material soobtained was triturated under diethyl ether. The resultant solid waswashed with diethyl ether and dried under vacuum to give7-methoxy-5-(N-methylpiperidin-4-yloxy)-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one(1.75 g); NMR Spectrum: (CDCl₃): 1.2 (s, 9H), 2.05 (br s, 4H), 2.3 (s,3H), 2.3-2.42 (m, 2H), 2.7-2.8 (m, 2H), 3.9 (s, 3H), 4.48 (m, 1H), 5.9(s, 2H), 6.5 (d, 1H), 6.71 (d, 1H), 8.18 (s, 1H).

[0709] A mixture of the material so obtained and a saturated methanolicammonia solution (100 ml) was stirred at ambient temperature for 15hours. The mixture was evaporated and the residue was triturated underdiethyl ether. The resultant precipitate was isolated, washed withdiethyl ether and dried under vacuum. There was thus obtained7-methoxy-5-(N-methylpiperidin-4-yloxy)-3,4-dihydroquinazolin-4-one(0.855 g); NMR Spectrum: (DMSOd₆) 1.7 (m, 2H), 1.9 (m, 2H), 2.15 (s,3H), 1.15-1.25 (m, 2H), 2.55-2.7 (m, 2H), 3.85 (s, 3H), 4.5 (m, 1H),6.55 (d, 1H), 6.65 (d, 1H), 7.89 (s, 1H), 11.62 (br s, 1H).

[0710] A mixture of7-methoxy-5-(N-methylpiperidin-4-yloxy)-3,4-dihydroquinazolin-4-one(0.65 g), triphenylphosphine (1.18 g), carbon tetrachloride (0.45 ml)and methylene chloride (25 ml) was stirred and heated to reflux for 2hours. The mixture was evaporated and the residue was purified by columnchromatography on silica using a 10:9:1 mixture of ethyl acetate,methylene chloride and a saturated methanolic ammonia solution aseluent. The material so obtained was triturated under pentane and theresultant solid was isolated and dried under vacuum. There was thusobtained 4-chloro-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline(0.5 g); NMR Spectrum: (CDCl₃) 1.95-2.15 (m, 4H), 2.3 (s, 3H), 2.3-2.45(m, 2H), 2.6-2.8 (m, 2H), 3.92 (s, 3H), 4.55 (br s, 1H), 6.56 (s, 1H),6.9 (s, 1H), 8.77 (s, 1H).

EXAMPLE 4

[0711] Using an analogous procedure to that described in Example 3, theappropriate 4-chloroquinazoline was reacted with the appropriate anilineto give the compound described in Table II. TABLE II

No. and Note (R¹)_(m) Q¹ (R²)_(n) [1] 7-methoxy N-methylpiperidin-4-yl2,4-dichloro- 5-methoxy [2] 7-methoxy N-methylpiperidin-4-yl2-fluoro-4-chloro- 5-methoxy [3] 7-(2-pyrrolidin-1-ylethoxy)4-tetrahydropyranyl 2,5-dimethoxy [4] 7-methoxy N-methylpiperidin-4-yl6-chloro- 2,3-methylenedioxy [5] 7-fluoro 4-tetrahydropyranyl 6-chloro-2,3-methylenedioxy [6] 7-(2-pyrrolidin-1-ylethoxy) 4-tetrahydropyranyl2,3-ethylenedioxy [7] 7-methoxy N-methylpiperidin-4-yl 2,3-ethylenedioxy[8] 7-methoxy piperidin-4-yl 2,3-ethylenedioxy

[0712] Notes

[0713] [1] The reaction product was obtained as the dihydrochloride saltfrom which the free base was isolated using an analogous procedure tothat described in Example 3. The free base gave the following data: NMRSpectrum: (CDCl₃) 2.0-2.15 (m, 2H), 2.15-2.3 (m, 4H), 2.32 (s, 3H), 2.85(m, 2H), 3.92 (s, 3H), 3.95 (s, 3H), 4.55 (m, 1H), 6.56 (d, 1H), 6.86(d, 1H), 7.42 (s, 1H), 8.31 (s, 1H), 8.56 (s, 1H), 9.87 (s, 1H); MassSpectrum: M+H⁺ 463 and 465.

[0714] [2] The reaction product was obtained as the dihydrochloridesalt; NMR Spectrum: (DMSOd₆ and NaOD) 1.9-2.1 (m, 2H), 2.2-2.35 (m, 2H),2.6 (s, 3H), 2.6 (m, 2H), 3.1-3.2 (m, 2H), 3.92 (s, 3H), 3.95 (s, 3H),4.95 (m, 1H), 6.92 (s, 1H), 6.95 (s, 1H), 7.6 (d, 1H), 8.6 (s, 1H), 8.7(br s, 1H); Mass Spectrum: M+H⁺ 447 and 449.

[0715] The 4-chloro-2-fluoro-5-methoxyaniline used as starting materialwas prepared as follows:

[0716] A 6N aqueous sodium hydroxide solution (17 ml) was added dropwiseto a stirred solution of4-chloro-2-fluoro-5-methoxycarbonyloxy-1-nitrobenzene (J. Med. Chem.,1999, 42, 5369; 25 g) in methanol (200 ml) which was cooled to 5° C. Thereaction mixture was stirred at ambient temperature for 30 minutes. A12N aqueous hydrochloric acid solution (8.5 ml) was added and themixture was evaporated. The residue was partitioned between methylenechloride and water. The organic layer was washed with brine, dried overmagnesium sulphate and evaporated to give4-chloro-2-fluoro-5-hydroxy-1-nitrobenzene (18.5 g); NMR Spectrum:(CDCl₃) 5.8 (br s, 1H), 7.35 (d, 1H), 7.75 (d, 1H).

[0717] Dimethyl sulphate (10.5 ml) was added to a stirred mixture of4-chloro-2-fluoro-5-hydroxy-1-nitrobenzene (14 g), potassium carbonate(13 g) and DMF (70 ml) and the reaction mixture was stirred at ambienttemperature for 16 hours. The mixture was poured into water (500 ml) andthe resultant precipitate was isolated and dried under vacuum. The solidso obtained was partitioned between methylene chloride and water. Theorganic layer was washed with brine, dried over magnesium sulphate andevaporated to give 4-chloro-2-fluoro-5-methoxy-1-nitrobenzene (14.1 g);NMR Spectrum: (CDCl₃) 3.94 (s, 3H), 7.4 (d, 1H), 7.6 (d, 1H).

[0718] A mixture of the material so obtained, platinum oxide (0.5 g) andethanol (250 ml) was stirred under 1.2 atmosphere pressure of hydrogenfor 2 hours. The mixture was filtered and the filtrate was evaporated.The residue was purified by column chromatography on silica usingmethylene chloride as eluent. There was thus obtained4-chloro-2-fluoro-5-methoxyaniline (8.5 g); NMR Spectrum: (CDCl₃) 3.7(br s, 2H), 3.81 (s, 3H), 6.38 (d, 1H), 7.02 (d, 1H), 7.28 (s, 1H).

[0719] [3] The reaction product was obtained as the dihydrochloridesalt; NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 1.85-2.0 (m, 4H), 2.0-2.15 (m,2H), 2.2-2.3 (m, 2H), 3.15-3.25 (m, 2H), 3.58 (t, 2H), 3.65-3.75 (m,4H), 3.78 (s, 3H), 3.95 (s, 3H), 4.02 (m, 2H), 4.6 (m, 2H), 5.2 (m, 1H),6.9 (m, 1H), 7.02 (d, 1H), 7.16 (d, 1H), 7.23 (d, 1H), 8.16 (d, 1H),8.98 (s, 1H); Mass Spectrum: M+H⁺ 495.

[0720] The4-chloro-7-(2-pyrrolidin-1-ylethoxy)-5-tetrahydropyran-4-yloxyquinazolineused as a starting material is described in Example 19, Note [6].

[0721] [4] The reaction product was obtained as the dihydrochloride saltfrom which the free base was isolated using an analogous procedure tothat described in Example 3. The free base gave the following data: NMRSpectrum: (CDCl₃) 2.0-2.15 (m, 2H), 2.15-2.3 (m, 2H), 2.3 (s, 3H),2.3-2.5 (m, 2H), 2.75 (m, 2H), 3.92 (s, 3H), 4.6 (m, 1H), 6.05 (s, 2H),6.50 (d, 1H), 6.72 (d, 1H), 6.84 (d, 1H), 6.97 (d, 1H), 8.52 (s, 1H),9.26 (s, 1H); Mass Spectrum: M+H⁺ 443 and 445.

[0722] [5] The reaction product was obtained as the dihydrochloride saltfrom which the free base was isolated using an analogous procedure tothat described in Example 3. The free base gave the following data: NMRSpectrum: (CDCl₃) 1.92-2.1 (m, 2H), 2.2-2.3 (m, 2H), 3.6-3.7 (m, 2H),4.0-4.1 (m, 2H), 4.8 (m, 1H), 6.1 (s, 2H), 6.7 (m, 1H), 6.75 (d, 1H),6.98 (d, 1H), 7.15 (m, 1H), 8.6 (s, 1H), 9.32 (s, 1H); Mass Spectrum:M+H⁺ 418 and 420.

[0723] The 4-chloro-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline usedas a starting material was prepared as follows:

[0724] A solution of 3,5-difluoroaniline (10.8 g) in a mixture of 12Naqueous hydrochloric acid solution (7.5 ml) and water (90 ml) was addedto a stirred mixture of chloral hydrate (9.2 ml), sodium sulphatedecahydrate (240 g) and water (210 ml). A solution of hydroxylaminehydrochloride (18.6 g) in water (90 ml) was then added and the mixturewas heated to 120° C. for 45 minutes. The mixture was cooled to ambienttemperature and the precipitate was isolated and dried under vacuum. Thematerial so obtained was added to concentrated sulphuric acid (60 ml)and the mixture was stirred and heated to 80-90° C. for 10 minutes. Themixture was cooled to ambient temperature and poured onto a 1:1 mixtureof ice and water (600 ml). The precipitate was isolated, washed withwater and dried under vacuum at 50° C. to give4,6-difluoro-2,3-dioxoindoline (14 g); NMR Spectrum: (DMSOd₆) 6.61 (m,1H), 6.9 (m, 1H).

[0725] Hydrogen peroxide (35% solution in water, 23 ml) was addeddropwise to a stirred solution of 4,6-difluoro-2,3-dioxoindoline (14 g)in a concentrated aqueous sodium hydroxide solution (33%, 115 ml) thatwas heated to 70° C. The mixture was heated to 70° C. for 15 minutes.The resultant mixture was cooled to 0° C. and the the mixture wasacidified to pH⁴ by the addition of concentrated aqueous hydrochloricacid. The mixture was extracted with ethyl acetate. The organic layerwas separated, washed with brine, dried over magnesium sulphate andevaporated to give 2-amino-4,6-difluorobenzoic acid (12 g); NMRSpectrum: (DMSOd₆) 6.25 (m, 1H), 6.38 (m, 1H).

[0726] Diethyl azodicarboxylate (26.7 ml) was added dropwise to astirred mixture of 2-amino-4,6-difluorobenzoic acid (26.6 g),triphenylphosphine (45 g), methanol (9 ml) and methylene chloride (350ml) that had been cooled to 5° C. The mixture was allowed to warm toambient temperature and was stirred for 2 hours. The reaction mixturewas poured onto a chromatography column loaded with silica and elutedwith methylene chloride. There was thus obtained methyl2-amino-4,6-difluorobenzoate (25.2 g); NMR Spectrum: (DMSOd₆) 3.8 (s,3H), 6.3 (m, 1H), 6.4 (m, 1H), 7.0 (br s, 2H); Mass Spectrum: M+H⁺ 188.

[0727] A mixture of methyl 2-amino-4,6-difluorobenzoate (47 g),formamidine acetate (79 g) and 2-methoxyethanol (750 ml) was stirred andheated to reflux for 10 hours. A second portion (26 g) of formamidineacetate was added and the mixture was heated to reflux for a further 2.5hours. The mixture was cooled to ambient temperature and evaporated. Theresidue was washed with diethyl ether and with water and dried undervacuum over phosphorus pentoxide. The filtrate was evaporated to drynessand the residue was triturated under diethyl ether. The resultant solidwas isolated and dried under vacuum. The two batches of solid werecombined and purified by column chromatography on silica using a 19:1mixture of methylene chloride and methanol as eluent. There was thusobtained 5,7-difluoro-3,4-dihydroquinazolin-4-one (33.7 g); NMRSpectrum: (DMSOd₆) 7.3-7.4 (m, 2H), 8.12 (s, 1H); Mass Spectrum: M+H⁺183.

[0728] Sodium hydride (60% dispersion in mineral oil; 0.6 g) was addedportionwise to a solution of 4-hydroxytetrahydropyran (0.78 g) in DMF(10 ml) that had been cooled to 5° C. The mixture was allowed to warm toambient temperature and was stirred for 15 minutes.5,7-Difluoro-3,4-dihydroquinazolin-4-one (0.9 g) was added and themixture was stirred at ambient temperature for 30 minutes. The mixturewas poured into water (100 ml) and, with vigorous stirring, glacialacetic acid was added to acidify the mixture to pH5. The resultant solidwas isolated, washed with water and with diethyl ether and dried undervacuum. There was thus obtained7-fluoro-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (1.1 g);NMR Spectrum: (DMSOd₆) 1.6-1.75 (m, 2H), 1.9-2.0 (m, 2H), 3.5-3.6 (m,2H), 3.85-3.95 (m, 2H), 4.8 (m, 1H), 6.9 (m, 1H), 7.05 (m, 1H), 8.0 (s,1H); Mass Spectrum: M+H⁺ 265.

[0729] A mixture of7-fluoro-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (1 g),phosphoryl chloride (4 ml), diisopropylethylamine (1.5 ml) and1,2-dichloroethane (15 ml) was stirred and heated to 80° C. for 3 hours.The mixture was evaporated to give4-chloro-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline which was usedwithout further purification.

[0730] [6] 2,3-Ethylenedioxyaniline (J. Med. Chem., 1995, 38, 4044) wasused as a starting material. The reaction product was obtained as thedihydrochloride salt; NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 1.8-2.0 (m,4H), 2.0-2.1 (m, 2H), 2.15-2.25 (m, 2H), 3.1-3.25 (m, 2H), 3.55 (m, 2H),3.6-3.75 (m, 4H), 4.0 (m, 2H), 4.32 (m, 2H), 4.42 (m, 2H), 4.58 (t, 2H),5.2 (m, 1H), 6.85 (d, 1H), 6.95 (m, 1H), 6.99 (d, 1H), 7.2 (d, 1H), 8.0(d, 1H), 8.94 (s, 1H); Mass Spectrum: M+H⁺ 493.

[0731] [7] The reaction product was obtained as the dihydrochloride saltfrom which the free base was isolated using an analogous procedure tothat described in Example 3. The free base gave the following data: NMRSpectrum: (CDCl₃) 1.95-2.1 (m, 2H), 2.15-2.3 (m, 4H), 2.3 (s, 3H), 2.9(m, 2H), 3.9 (s, 3H), 4.32 (m, 2H), 4.4 (m, 2H), 4.52 (m, 1H), 6.5 (d,1H), 6.65 (m, 1H), 6.8 (d, 1H), 6.92 (m, 1H), 8.3 (d, 1H), 8.6 (s, 1H),10.05 (s, 1H); Mass Spectrum: M+H⁺ 423.

[0732] [8] The reactants were5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-chloro-7-methoxyquinazolineand 2,3-ethylenedioxyaniline. The precipitate from the reaction mixturewas isolated, washed in turn with isopropanol, ethyl acetate and diethylether and dried under vacuum. The material so obtained was dissolved ina 2M solution of hydrogen chloride in diethyl ether and the mixture wasstirred at ambient temperature for 2 hours. The resultant solid wasisolated, washed with diethyl ether and dried under vacuum. The reactionproduct so obtained was obtained a dihydrochloride salt; NMR Spectrum:(DMSOd₆ and CF₃CO₂D) 2.0-2.15 (m, 2H), 2.35-2.55 (m, 2H), 3.2 (m, 2H),3.45 (m, 2H), 4.02 (s, 3H), 4.4 (m, 2H), 4.52 (m, 2H), 5.2 (m, 1H), 6.85(d, 1H), 6.98 (m, 2H), 7.2 (d, 1H), 8.05 (d, 1H), 8.98 (s, 1H); MassSpectrum: M+H⁺ 409.

[0733] The5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-chloro-7-methoxyquinazolineused as a starting material is described in Example 33.

EXAMPLE 54-(5-chloronaphth-1-ylamino)-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazolinedihydrochloride

[0734] A mixture of4-chloro-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline (0.08 g),5-chloro-1-naphthylamine (0.055 g), 6.2M hydrogen chloride inisopropanol (0.044 ml) and isopropanol (3 ml) was stirred and heated toreflux for 2 hours. The mixture was cooled to ambient temperature andthe precipitate was isolated, washed with diethyl ether and dried undervacuum. There was thus obtained the title compound (0.129 g), a portionof which was treated with a saturated methanolic ammonia solution. Themixture was filtered and the filtrate was evaporated to give the freebase; NMR Spectrum: (CDCl₃) 1.9-2.1 (m, 4H), 2.22 (s, 3H), 2.25-2.4 (m,2H), 2.6-2.7 (m, 2H), 3.94 (s, 3H), 4.7 (br s, 1H), 6.6 (s, 1H), 6.9 (s,1H), 7.4 (m, 1H), 7.62 (d, 1H), 7.7 (m, 1H), 8.0 (m, 2H), 8.25 (d, 1H),8.46 (s, 1H), 9.9 (br s, 1H); Mass Spectrum: M+H⁺ 449 and 451.

EXAMPLE 64-(3-chlorobenzofuran-7-ylamino)-7-methoxy-5-N-methylpiperidin-4-yloxy)quinazolinedihydrochloride

[0735] Using an analogous procedure to that described in Example 5,4-chloro-7-methoxy-5-N-methylpiperidin-4-yloxy)quinazoline was reactedwith 7-amino-3-chlorobenzofuran to give the title compound, a portion ofwhich was treated with a saturated methanolic ammonia solution. Themixture was filtered and the filtrate was evaporated to give the freebase; NMR Spectrum: (CDCl₃) 2.0-2.4 (m, 6H), 2.33 (s, 3H), 2.9 (m, 2H),3.93 (s, 3H), 4.6 (m, 1H), 6.56 (s, 1H), 6.9 (s, 1H), 7.3-7.4 (m, 2H),7.7 (br s, 1H ), 8.64 (s, 1H), 8.7 (d, 1H), 10.3 (br s, 1H); MassSpectrum: M+H⁺ 439 and 441.

[0736] The 7-amino-3-chlorobenzofuran used as a starting material wasprepared as follows:

[0737] For a 30 minute period, chlorine gas was bubbled through asolution of 7-nitrobenzofuran (1.2 g) in glacial acetic acid (12 ml)which had been cooled at 18° C. The resultant mixture was evaporated andthe residue was partitioned between diethyl ether and water. The organiclayer was washed in turn with a saturated aqueous sodium bicarbonatesolution, water and a saturated aqueous sodium chloride solution, dried(MgSO₄) and evaporated. The residue was purified by columnchromatography on silica to give a mixture of cis and trans2,3-dichloro-7-nitro-2,3-dihydrobenzofuran. The material so obtained wasdissolved in ethanol (2 ml) and a solution of 0.8M potassium hydroxidein ethanol (2.7 ml) was added. The mixture was stirred at ambienttemperature for 75 minutes. The mixture was evaporated to remove theethanol. The residue was diluted with water and the mixture wasacidified to pH2 by the addition of concentrated hydrochloric acid. Themixture was extracted with diethyl ether. The organic extract was washedwith water and with a saturated aqueous sodium chloride solution, dried(MgSO4) and evaporated. There was thus obtained3-chloro-7-nitrobenzofuran (0.7 g); NMR Spectrum: (DMSOd₆) 7.63 (m, 1H),8.12 (d, 1H), 8.3 (d, 1H), 8.65 (s, 1H); Mass Spectrum: M+H⁺ 197 and199.

[0738] A suspension of hydrazine hydrate (0.049 ml) and Raney nickel(0.01 g) in methanol (2 ml) was heated to 60° C. and added dropwise to amixture of 3-chloro-7-nitrobenzofuran (0.04 g) and methanol (4 ml). Theresultant mixture was heated to reflux for 10 minutes, filtered andevaporated. The residue was partitioned between methylene chloride andwater. The organic layer was washed with water, dried (MgSO₄) andevaporated. The residue was purified by column chromatography on silicausing a 1:1 mixture of methylene chloride and petroleum ether as eluent.There was thus obtained 3-chloro-7-aminobenzofuran (0.021 g); NMRSpectrum: (DMSOd₆ and CF₃COOD) 6.65 (d, 1H), 6.75 (d, 1H), 7.05 (m, 1H),8.2 (s, 1H); Mass Spectrum: M+H⁺ 167.

EXAMPLE 74-(2,3-methylenedioxyanilino)-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazolinedihydrochloride

[0739] Using an analogous procedure to that described in Example 5,4-chloro-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline was reactedwith 2,3-methylenedioxyaniline (J. Med. Chem., 1979, 22, 1354) to givethe title compound, a portion of which was treated with a saturatedmethanolic ammonia solution. The mixture was filtered and the filtratewas evaporated to give the free base; NMR Spectrum: (CDCl₃) 2.0-2.1 (m,2H), 2.15-2.3 (m, 4H), 2.31 (s, 3H), 2.85 (m, 2H), 3.91 (s, 3H), 6.01(s, 2H), 6.5 (d, 1H), 6.68 (d, 1H), 6.82 (d, 1H), 6.91 (m, 1H), 8.0 (d,1H), 8.6 (s, 1H), 9.72 (s, 1H); Mass Spectrum: M+H⁺ 409.

EXAMPLE 84-(2-chloro-5-methoxyanilino)-5-(N-methylpiperidin-4-ylmethoxy)quinazoline

[0740] A mixture of5-[N-(tert-butoxycarbonyl)piperidin-4-ylmethoxy]-4-(2-chloro-5-methoxyanilino)quinazoline(0.2 g), a concentrated aqueous formaldehyde solution (37%, 0.4 ml) andformic acid (4 ml) was stirred and heated to 100° C. for 2.5 hours. Themixture was cooled to ambient temperature and evaporated. The residuewas triturated under diethyl ether and the resultant solid was isolatedand dried under vacuum. There was thus obtained4-(2-chloro-5-methoxyinilino)-5-(N-methylpiperidin-4-ylmethoxy)quinazoline,as a formic acid salt (0.09 g); NMR Spectrum: (CDCl₃) 1.8-2.0 (m, 2H),2.05-2.15 (m, 2H), 2.35 (m, 1H), 2.6 (t, 2H), 3.55 (d, 2H), 3.93 (s,3H), 4.21 (d, 2H), 6.68 (m, 1H), 6.95 (d, 1H), 7.31 (d, 1H), 7.54 (d,1H), 7.7 (m, 1H), 8.35 (br s, 1H), 8.39 (d, 1H), 8.7 (s, 1H); MassSpectrum: M+H⁺ 413.

EXAMPLE 94-(2-bromo-5-methoxyanilino)-5-(N-methylpiperidin-4-ylmethoxy)quinazoline

[0741] Using an analogous procedure to that described in Example 8,4-(2-bromo-5-methoxyanilino)-5-[N-(tert-butoxycarbonyl)piperidin-4-ylmethoxy]quinazoline(0.22 g)was reacted with concentrated aqueous formaldehyde solution (0.4ml) to give the title compound, as a formic acid salt (0.183 g); NMRSpectrum: (CDCl₃) 1.7-1.9 (m, 2H), 2.06 (d, 2H), 2.2 (m, 1H), 2.58 (t,2H), 2.68 (s, 3H), 3.51 (d, 2H), 3.8 (s, 3H), 4.24 (d, 2H), 6.64 (m,1H), 6.94 (d, 1H), 7.48 (d, 1H), 7.54 (d, 1H), 7.69 (m, 1H), 8.2 (d,1H), 8.3 (br s, 1H), 8.69 (s, 1H), 9.94 (s, 1H); Mass Spectrum: M+H⁺ 457and 459.

EXAMPLE 104-(2-bromo-5-methoxyanilino)-5-piperidin-4-ylmethoxyquinazoline

[0742] A mixture of4-(2-bromo-5-methoxyanilino)-5-[N-(tert-butoxycarbonyl)piperidin-4-ylmethoxy]quinazoline(0.108 g), trifluoroacetic acid (1 ml) and methylene chloride (1 ml) wasstirred at ambient temperature for 1.5 hours. The mixture was evaporatedand the residue was triturated under diethyl ether. The resultant solidwas isolated and dried under vacuum. The solid was dissolved inmethylene chloride and few drops of a saturated methanolic ammoniasolution was added. The solution was poured onto a chromatography columnfilled with silica and eluted with a 97:3 mixture of methylene chlorideand a saturated methanolic ammonia solution. There was thus obtained thetitle compound (0.082 g); NMR Spectrum: (CDCl₃) 1.2-1.4 (m, 2H), 1.9 (d,2H), 2.3 (m, 1H), 2.65 (t, 2H), 3.12 (d, 2H), 3.84 (s, 3H), 4.2 (d, 2H),6.61 (m, 1H), 6.93 (d, 1H), 7.5 (d, 2H), 7.68 (m, 1H), 8.22 (d, 1H),8.68 (s, 1H); Mass Spectrum: M+H⁺ 443 and 445.

EXAMPLE 114-(2-chloro-5-methoxyanilino)-7-hydroxy-5-(3-morpholinopropoxy)quinazoline

[0743] A mixture of7-benzyloxy4-(2-chloro-5-methoxyanilino)-5-(3-morpholinopropoxy)quinazoline(0.185 g), 10% palladium on charcoal catalyst (0.018 g), ethanol (2.5ml), THF (2.5 ml) and DMF (1 ml) was stirred under an atmospherepressure of hydrogen for 16 hours. The mixture was filtered and thefiltrate was evaporated. The residue was purified by columnchromatography on silica using a 9:1 mixture of methylene chloride and asaturated methanolic ammonia solution as eluent. There was thus obtainedthe title compound (0.045 g); NMR Spectrum: (DMSOd₆) 2.05 (m, 2H), 2.35(br s, 4H), 2.45 (t, 2H), 3.55 (t, 4H), 3.8 (s, 3H), 4.42 (t, 2H), 6.7(d, 2H), 7.45 (d, 1H), 8.3 (s, 1H), 8.45 (s, 1H), 10.05 (s, 1H); MassSpectrum: M+H⁺ 445.

EXAMPLE 124-(2-chloro-5-methoxyanilino)-5,7-di-(3-morpholinopropoxy)quinazoline

[0744] Di-tert-butyl azodicarboxylate (0.035 g) was added dropwise to astirred mixture of4-(2-chloro-5-methoxyanilino)-7-hydroxy-5-(3-morpholinopropoxy)quinazoline(0.045 g), 4-(3-hydroxypropyl)morpholine (0.016 g), triphenylphosplhine(0.04 g) and methylene chloride (1 ml). The reaction mixture was stirredat ambient temperature for 10 minutes. The mixture was evaporated andthe residue was purified by column chromatography on silica using a9:10:1 mixture of methylene chloride, ethyl acetate and a saturatedmethanolic ammonia solution as eluent. The material so obtained wastriturated under diethyl ether. The resultant solid was isolated, washedwith diethyl ether and dried under vacuum to give the title compound(0.018 g); NMR Spectrum: (DMSOd₆ and CF₃COOD) 2.2-2.4 (m, 4H), 3.15 (m,4H), 3.35 (m, 4H), 3.5 (m, 4H), 3.7 (m, 4H), 3.8 (s, 3H), 4.02 (t, 4H),4.35 (t, 2H), 4.6 (t, 2H), 6.95 (s, 1H), 7.03 (s, 1H), 7.05 (m, 1H), 7.5(s, 1H), 7.6 (d, 1H), 8.88 (s, 1H); Mass Spectrum: M+H⁺ 572 and 574.

EXAMPLE 134-(2-chloro-5-methoxyanilino)-7-hydroxy-5-(3-pyrrolidin-1-ylpropoxy)quinazoline

[0745] A mixture of7-benzyloxy-4-(2-chloro-5-methoxyanilino)-5-(3-pyrrolidin-1-ylpropoxy)quinazoline(0.68 g), 10% palladium on charcoal catalyst (0.16 g), ethanol (13 ml)and THF (13 ml) was stirred under 5 atmospheres pressure of hydrogen for16 hours. The mixture was filtered and the filtrate was evaporated, Theresidue was triturated under methanol. The resulatnt solid was isolated,washed with diethyl ether and dried under vacuum. There was thusobtained the title compound (0.405 g); NMR Spectrum: (DMSOd₆) 1.65 (brs, 4H), 2.1 (m, 2H), 2.4 (br s, 4H), 2.55 (t, 2H), 3.8 (s, 3H), 4.4 (t,2H), 6.7 (m, 2H), 6.75 (m, 1H), 7.48 (d, 1H), 8.3 (d, 1H), 8.4 (s, 1H),10.05 (s, 1H).

EXAMPLE 14

[0746] Using an analogous procedure to that described in Example 12, theappropriate 7-hydroxy-substituted quinazoline was reacted with theappropriate alcohol to give the compounds described in Table III. TABLEIII

No. & Note (R¹)_(m) Q¹ (R²)_(n) [1] 7-(3-morpholinopropoxy)3-pyrrolidin-1-ylpropyl 2-chloro-5-methoxy [2]7-[3-(4-methylpiperiazin-1- 3-pyrrolidin-1-ylpropyl 2-chloro-5-methoxyyl)propoxy] [3] 7-(2-methoxyethoxy) 3-pyrrolidin-1-ylpropyl2-chloro-5-methoxy [4] 7-[2-(2-methoxyethoxy)ethoxy]3-pyrrolidin-1-ylpropyl 2-chloro-5-methoxy [5] 7-isopropoxy4-piperidinyl 2-bromo-5-methoxy [6] 7-(3-methylsulphonyl)propoxy4-piperidinyl 2-bromo-5-methoxy [7] 7-(2-pyridylmethoxy)N-(2-pyridylmethyl)- 2-bromo-5-methoxy piperidin-4-yl [8]7-[3-(4-methylpiperazin-1- 4-tetrahydropyranyl 2-chloro-5-methoxyyl)propoxy] [9] 7-(3-morpholinopropoxy) 4-tetrahydropyranyl2-chloro-5-methoxy [10] 7-(N-methylpiperidin-4-yloxy)4-tetrahydropyranyl 2-bromo-5-methoxy [11] 7-(2-pyrrolidin-1-ylethoxy)4-tetrahydropyranyl 2-bromo-5-methoxy [12] 7-(3-pyrrolidin-1-ylpropoxy)4-tetrahydropyranyl 2-bromo-5-methoxy [13] 7-(2-piperidinoethoxy)4-tetrahydropyranyl 2-bromo-5-methoxy [14] 7-[2-(4-methylpiperazin-1-4-tetrahydropyranyl 2-bromo-5-methoxy yl)ethoxy] [15]7-[3-(4-methylpiperazin-1- 4-tetrahydropyranyl 2-bromo-5-methoxyyl)propoxy] [16] 7-(2-(2-morpholinomethyl- 4-tetrahydropyranyl2-bromo-5-methoxy 5-methylimidazol-1-yl)ethoxy] [17]7-{2-[2-(N,N-dimethylcarbamoyl)- 4-tetrahydropyranyl 2-bromo-5-methoxypyrrolidin-1-yl]ethoxy} [18] 7-{3-[2-(N,N-dimethylcarbamoyl)-4-tetrahydropyranyl 2-bromo-5-methoxy pyrrolidin-1-yl]propoxy} [19]7-[2-(2,5-dimethoxymethyl- 4-tetrahydropyranyl 2-bromo-5-methoxypyrrolidin-1-yl)ethoxy] [20] 7-[2-(4-pyridyloxy)ethoxy]4-tetrahydropyranyl 2-bromo-5-methoxy [21] 7-(3-morpholinopropoxy)cyclohexyl 2-chloro-5-methoxy [22] 7-(2-pyrrolidin-1-ylethoxy)cyclopentyl 2,4-dichloro- 5-methoxy [23] 7-(3-morpholinopropoxy)isopropyl 2-chloro-5-methoxy [24] 7-[3-(4-methylpiperiazin-1- isopropyl2-chloro-5-methoxy yl)propoxy] [25] 7-(2-pyrrolidin-1-ylethoxy)4-tetrahydropyranyl 2,3-methylenedioxy [26] 7-(3-pyrrolidin-1-ylpropoxy)4-tetrahydropyranyl 2,3-methylenedioxy [27] 7-(3-pyridylmethoxy)4-piperidinyl 2-bromo-5-methoxy [28] 7-(2-pyrrolidin-1-ylethoxy)4-tetrahydropyranyl 2,4-dichloro- 5-methoxy [29]7-(3-pyrrolidin-1-ylpropoxy) 4-tetrahydropyranyl 2,4-dichloro- 5-methoxy[30] 7-(2-piperidinoethoxy) 4-tetrahydropyranyl 2,4-dichloro- 5-methoxy[31] 7-[2-(4-methylpiperazin-1-ylethoxy] 4-tetrahydropyranyl2,4-dichloro- 5-methoxy [32] 7-(2-morpholinoethoxy) 4-tetrahydropyranyl2,4-dichloro- 5-methoxy [33] 7-{2-[2-(N-methylcarbamoyl)-4-tetrahydropyranyl 2,4-dichloro- pyrrolidin-1-yl]ethoxy} 5-methoxy [34]7-[2-(2-carbamoylpyrrolidin-1- 4-tetrahydropyranyl 2,4-dichloro-yl)ethoxy] 5-methoxy [35] 7-[2-(2-morpholinocarbonyl-4-tetrahydropyranyl 2,4-dichloro- pyrrolidin-1-yl)ethoxy] 5-methoxy [36]7-{2-[2-(4-methylpiperazin-1- 4-tetrahydropyranyl 2,4-dichloro-ylcarbonyl)pyrrolidin-1-yl]ethoxy} 5-methoxy [37]7-{2-[2-(pyrrolidin-1-ylcarbonyl)- 4-tetrahydropyranyl 2,4-dichloro-pyrrolidin-1-yl]ethoxy} 5-methoxy [38] 7-[2-(2-piperidinocarbonyl-4-tetrahydropyranyl 2,4-dichloro- pyrrolidin-1-yl)ethoxy] 5-methoxy [39]7-[2-(2-methylpyrollidin-1- 4-tetrahydropyranyl 2,4-dichloro- yl)ethoxy]5-methoxy [40] 7-[2-(2-methoxymethylpyrrolidin-1- 4-tetrahydropyranyl2,4-dichloro- yl)ethoxy] 5-methoxy [41] 7-[2-(4-pyridyloxy)ethoxy]4-tetrahydropyranyl 2,4-dichloro- 5-methoxy [42] 7-(3-pyridylmethoxy)4-tetrahydropyranyl 2,4-dichloro- 5-methoxy [43] 7-(4-pyridylmethoxy)4-tetrahydrpyranyl 2,4-dichloro- 5-methoxy [44]7-(N-methylpiperidin-4-yloxy) 4-tetrahydropyranyl 2,4-dichloro-5-methoxy [45] 7-{2-[2-(N-methylcarbamoyl)- 4-tetrahydropyranyl2-bromo-5-methoxy pyrrolidin-1-yl]ethoxy} [46]7-[2-(2-morpholinocarbonyl- 4-tetrahydropyranyl 2-bromo-5-methoxypyrrolidin-1-yl)ethoxy] [47] 7-{2-[2-(4-mthylpiperazin-1-4-tetrahydropyranyl 2-bromo-5-methoxy ylcarbonyl)pyrrolidin-1-yl]ethoxy}[48] 7-{2-[2-(pyrrolidin-1-ylcarbonyl)- 4-tetrahydropyranyl2-bromo-5-methoxy pyrrolidin-1-yl]ethoxy} [49]7-[2-(2-piperidinocarbonyl- 4-tetrahydropyranyl 2-bromo-5-methoxypyrrolidin-1-yl)ethoxy] [50] 7-[2-(2-carbamoylpyrrolidin-1-4-tetrahydropyranyl 2-bromo-5-methoxy yl)ethoxy] [51]7-[2-(2-methylpyrrolidin-1- 4-tetrahydrpyranyl 2-bromo-5-methoxyyl)ethoxy] [52] 7-[2-(2-methoxymethylpyrrolid-1- 4-tetrahydropyranyl2-bromo-5-methoxy yl)ethoxy] [53] 7-(3-pyridylmethoxy)4-tetrahydropyranyl 2-bromo-5-methoxy [54] 7-(4-pyridylmethoxy)4-tetrahydropyranyl 2-bromo-5-methoxy [55] 7-isopropoxy 4-piperidinyl6-chloro- 2,3-methylenedioxy [56] 7-ethoxy 4-piperidinyl 6-chloro-2,3-methylenedioxy [57] 7-isobutoxy 4-piperidinyl 6-chloro-2,3-methylenedioxy [58] 7-(2-fluoroethoxy) 4-piperidinyl 6-chloro-2,3-methylenedioxy [59] 7-[2-(2,5-dimethoxymethyl- 4-tetrahydropyranyl2,3-methylenedioxy pyrrolidin-1-yl)ethoxy] [60]7-[2-(4-pyridyloxy)ethoxy] 4-tetrahydropyranyl 2,3-methylenedioxy [61]7-(3-pyridylmethoxy) 4-tetrahydropyranyl 2,3-methylenedioxy [62]7-(4-pyridylmethoxy) 4-tetrahydropyranyl 2,3-methylenedioxy [63]7-{2-[2-(N-methylcarbamoyl)- 4-tetrahydropyranyl 2,3-methylenedioxypyrrolidin-1-yl]ethoxy} [64] 7-[2-(2-morpholinocarbonyl-4-tetrahydropyranyl 2,3-methylenedioxy pyrrolidin-1-yl)ethoxy] [65]7-{2-[2-(4-methylpiperazin-1- 4-tetrahydropyranyl 2,3-methylenedioxyylcarbonyl)pyrrolidin-1-yl]ethoxy} [66]7-{2-[2-(pyrrolidin-1-ylcarbonyl)- 4-tetrahydropyranyl2,3-methylenedioxy pyrrolidin-1-yl]ethoxy} [67]7-[2-(2-piperidinocarbonyl- 4-tetrahydropyranyl 2,3-methylenedioxypyrrolidin-1-yl)ethoxy] [68] 7-[2-(2-carbamoylpyrrolidin-1-4-tetrahydropyranyl 2,3-methylenedioxy yl)ethoxy] [69]7-[2-(2-methylpyrrolidin-1- 4-tetrahydropyranyl 2,3-methylenedioxyyl)ethoxy] [70] 7-[2-(2-methoxymethylpyrrolidin-1- 4-tetrahydropyranyl2,3-methylenedioxy yl)ethoxy] [71] 7-(3-piperazin-1-ylpropoxy)4-tetrahydropyranyl 6-chloro- 2,3-methylenedioxy [72]7-[3-(4-methylpiperazin-1- 4-tetrahydropyranyl 6-chloro- yl)propoxy]2,3-methylenedioxy [73] 7-[2-(4-methylpiperazin-1- 4-tetrahydropyranyl6-chloro- yl)ethoxy] 2,3-methylenedioxy [74] 7-(2-piperidinoethoxy)4-tetrahydropyranyl 6-chloro- 2,3-methylenedioxy [75]7-(2-piperidin-4-ylethoxy) 4-tetrahydropyranyl 6-chloro-2,3-methylenedioxy [76] 7-[2-(4-pyridyloxy)ethoxy] 4-tetrahydropyranyl6-chloro- 2,3-methylenedioxy [77] 7-0[N-(tert-butoxycarbonyl)piperidin-4-tetrahydropyranyl 6-chloro- 4-ylmethoxy] 2,3-methylenedioxy [78]7-(3-pyrrolidin-1-ylpropoxy) cyclopentyl 2,3-methylenedioxy [79]7-[3-(4-methylpiperazin-1- cyclopentyl 2,3-methylenedioxy yl)propoxy][80] 7-[2-(4-methylpiperazin-1- cyclopentyl 2,3-methylenedioxyyl)ethoxy] [81] 7-(2-piperidinoethoxy) cyclopentyl 2,3-methylenedioxy[82] 7-{2-[2-(4-methylpiperazin-1- cyclopentyl 2,3-methylenedioxyylcarbonyl)pyrrolidin-1-yl]ethoxy} [83] 7-piperidin-4-ylmethoxy)cyclopentyl 2,3-methylenedioxy [84] 7-(3-piperazin-1-ylpropoxy)cyclopentyl 2,3-methylenedioxy

[0747] Notes

[0748] [1] The reaction product was treated with a 6M solution ofhydrogen chloride in diethyl ether (5 ml) at ambient temperature for 30minutes. The resultant solid was isolated, washed with isopropanol andwith diethyl ether and dried under vacuum to give the product as thetrihydrochloride salt; NMR Spectrum: (DMSOd₆ and CF₃COOD) 1.8-2.1 (m,4H), 2.35 (m, 4H), 3.05 (m, 2H), 3.15 (t, 2H), 3.35 (m, 4H), 3.55 (m,4H), 3.8 (s, 3H), 3.85 (t, 2H), 4.05 (d, 2H), 4.4 (t, 2H), 4.7 (t, 2H),7.0-7.15 (m, 3H), 7.52 (d, 1H), 7.56 (d, 1H), 8.86 (s, 1H); Massspectrum: M+H⁺ 556 and 558.

[0749] [2] The reaction product was treated with a 6M solution ofhydrogen chloride in diethyl ether (5 ml) at ambient temperature for 30minutes. The resultant solid was isolated, washed with isopropanol andwith diethyl ether and dried under vacuum to give the product as thetrihydrochloride salt; NMR Spectrum: (DMSOd₆ and CF₃COOD) 1.8-2.05 (m,4H), 2.4 (m, 2H), 2.95 (s, 3H), 3.02 (m, 2H), 3.2-3.65 (m, 12H), 3.8 (t,2H), 3.85 (s, 3H), 4.4 (t, 2H), 4.7 (t, 2H), 7.02 (s, 1H), 7.05 (m, 1H),7.1 (s, 1H), 7.5 (s, 1H), 7.6 (d, 1H), 7.95 (s, 1H).

[0750] [3] The reaction product was treated with a 6M solution ofhydrogen chloride in diethyl ether (5 ml) at ambient temperature for 30minutes. The resultant solid was isolated, washed with isopropanol andwith diethyl ether and dried under vacuum to give the product as thedihydrochloride salt; NMR Spectrum: (DMSOd₆ and CF₃COOD) 1.85-2.1 (m,4H), 2.38 (m, 2H), 3.05 (m, 2H), 3.35 (t, 2H), 3.4 (s, 3H), 3.6 (m, 2H),3.8 (s, 3H), 3.85 (m, 2H), 4.4 (t, 2H), 4.65 (t, 2H), 7.0 (s, 1H), 7.05(m, 1H), 7.12 (s, 1H), 7.52 (d, 1H), 7.6 (d, 1H), 8.87 (s, 1H); MassSpectrum: M+H⁺ 487 and 489.

[0751] [4] The reaction product was treated with a 6M solution ofhydrogen chloride in diethyl ether (5 ml) at ambient temperature for 30minutes. The resultant solid was isolated, washed with isopropanol andwith diethyl ether and dried under vacuum to give the product as thedihydrochloride salt; NMR Spectrum: (DMSOd₆ and CF₃COOD) 1.8-2.05 (m,4H), 2.35 (m, 2H), 3.0 (m, 2H), 3.25 (s, 3H), 3.35 (t, 2H), 3.5 (t, 2H),3.55 (m, 2H), 3.65 (t, 2H), 3.8 (s, 3H), 3.85 (m, 2H), 4.35 (m, 2H),4.65 (t, 2H), 7.0 (s, 1H), 7.05 (m, 1H), 7.12 (s, 1H), 7.45 (s, 1H),7.57 (d, 1H), 8.85 (s, 1H); Mass Spectrum: M+H⁺ 531 and 533.

[0752] [5] The reaction mixture was stirred at ambient temperature for 2hours. The reaction product was treated with 6M hydrogen chloride inisopropanol to give4-(2-bromo-5-methoxyanilino)-7-isopropoxy-5-piperidin-4-yloxyquinazolinedihydrochloride, a portion of which was converted to the free base usingan analogous procedure to that described in Example 3. The free basegave the following data: NMR Spectrum: (CDCl₃) 1.45 (d, 6H), 1.8-2.0 (m,2H), 2.25 (d, 2H), 2.75 (m, 2H), 3.2 (m, 2H), 3.82 (s, 3H), 4.65 (m,1H), 4.75 (m, 1H), 6.52 (d, 1H), 6.65 (m, 1H), 6.85 (d, 1H), 7.5 (d,1H), 7.92 (d, 1H), 8.52 (s, 1H), 9.72 (s, 1H); Mass Spectrum: M+H⁺ 487and 489.

[0753] The4-(2-bromo-5-methoxyanilino)-7-hydroxy-5-piperidin-4-yloxyquinazolineused as a starting material is described in Example 20 hereinafter.

[0754] [6] The reaction mixture was stirred at ambient temperature for 1hour whereafter a second portion of each of di-tert-butylazodicarboxylate and triphenylphosphine were added and the reactionmixture was stirred at ambient temperature for 30 minutes. The reactionproduct was dissolved in methanol containing potassium carbonate andheated to reflux for 15 minutes. The mixture was filtered and thefiltrate was evaporated to give the required product; NMR Spectrum:(CDCl₃) 1.85-2.0 (m, 2H), 2.25 (d, 2H), 2.42 (m, 2H), 2.8 (m, 2H), 3.0(s, 3H), 3.21 (m, 2H), 3.3 (m, 2H), 3.82 (s, 3H), 4.25 (m, 2H), 4.65 (m,1H), 6.55 (d, 1H), 6.62 (m, 1H), 6.82 (d, 1H), 7.5 (d, 1H), 7.9 (d, 1H),8.52 (s, 1H), 9.75 (s, 1H); Mass Spectrum: M+H⁺ 565 and 567.

[0755] [7] The reactants were4-(2-bromo-5-methoxyanilino)-7-hydroxy-5-piperidin-4-yloxyquinazolineand 2-pyridylmethanol. The reaction mixture was stirred at ambienttemperature for 1 hour whereafter a second portion of each ofdi-tert-butyl azodicarboxylate and triphenylphosphine were added and thereaction mixture was stirred at ambient temperature for 30 minutes. Thereaction product was dissolved in methanol containing potassiumcarbonate and heated to reflux for 15 minutes. The mixture was filteredand the filtrate was evaporated to give the required product; NMRSpectrum: (CDCl₃) 2.05-2.2 (m, 2H), 2.2-2.3 (m, 2H), 2.35 (m, 2H), 2.92(d, 2H), 3.68 (s, 3H), 3.82 (s, 3H), 4.6 (m, 1H), 5.32 (s, 2H), 6.62 (m,1H), 6.7 (d, 1H), 6.92 (d, 1H), 7.2 (m, 1H), 7.4 (d, 1m), 7.5 (m, 2H),7.65 (m, 1H), 7.75 (m, 1H), 7.88 (d, 1H), 8.52 (s, 1H), 8.55 (m, 2H),8.65 (d, 1H), 9.72 (s, 1H); Mass Spectrum: M+H⁺ 627 and 629.

[0756] [8] The reaction mixture was stirred at ambient temperature for 2hours. The reaction product, obtained as the free base, gave thefollowing data: NMR Spectrum: (CDCl₃) 2.0-2.15 (m, 6H), 2.3 (s, 3H),2.35-2.7 (m, 10H), 3.6 (t, 2H), 3.85 (s, 3H), 4.0-4.2 (m, 4H), 4.75 (m,1H), 6.6 (s, 1H), 6.7 (m, 1H), 6.9 (s, 1H), 7.32 (d, 1H), 8.2 (s, 1H),8.58 (s, 1H), 9.85 (s, 1H); Mass Spectrum: M+H⁺ 542 and 544.

[0757] The4-(2-chloro-5-methoxyanilino)-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline,used as a starting material, is described in Example 21.

[0758] [9] The reaction mixture was stirred at ambient temperature for 2hours. The reaction product, obtained as the free base, gave thefollowing data: NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 1.85-2.0 (s, 2H),2.18 (d, 2H), 2.2-2.3 (m, 2H), 3.15 (m, 2H), 3.3-3.4 (m, 2H), 3.5 (d,2H), 3.7 (t, 2H), 3.8 (s, 3H), 3.95 (m, 2H), 4.05 (d, 2H), 4.3 (t, 2H),5.15 (m, 1H), 6.9 (s, 1H), 7.02 (m, 1H), 7.1 (s, 1H), 7.6 (m, 2H), 8.9(s, 1H); Mass Spectrum: M+H⁺ 529 and 531.

[0759] [10] The reaction mixture was stirred at ambient temperature for2 hours. The reaction product was treated with 6M hydrogen chloride indiethyl ether to give the dihydrochloride salt. A portion thereof wastreated with a saturated methanolic ammonia solution, the mixture wasfiltered and the filtrate evaporated to give the free base which gavethe following data: NMR Spectrum: (CDCl₃) 1.8-2.0 (m, 2H), 2.0-2.2 (m,4H), 2.2-2.3 (m, 4H), 2.33 (s, 3H), 2.78 (m, 2H), 3.6 (m, 2H), 3.84 (s,3H), 4.08 (m, 2H), 4.45 (m, 1H), 4.75 (m, 1H), 6.55 (s, 1H), 6.65 (m,1H), 6.85 (d, 1H), 7.5 (d, 1H), 7.92 (d, 1H), 8.52 (s, 1H), 9.7 (s, H);Mass Spectrum: M+H⁺ 543 and 545.

[0760] The4-(2-bromo-5-methoxyanilino)-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline,used as a starting material, is described in Example 24.

[0761] [11] The reaction mixture was stirred at ambient temperature for2 hours. The reaction product was treated with 6M hydrogen chloride indiethyl ether to give the dihydrochloride salt. A portion thereof wastreated with a saturated methanolic ammonia solution, the mixture wasfiltered and the filtrate evaporated to give the free base which gavethe following data: NMR Spectrum: (CDCl₃) 1.85 (m, 4H), 2.1 (m, 2H),2.22 (d, 2H), 2.65 (m, 4H), 2.98 (t, 2H), 3.58 (t, 2H), 3.85 (s, 3H),4.05 (m, 2H), 4.22 (t, 2H), 4.75 (m, 1H), 6.65 (m, 2H), 6.87 (s, 1H),7.5 (d, 1H), 7.95 (s, 1H), 8.55 (s, 1H), 9.7 (s, 1H); Mass Spectrum:M+H⁺ 543 and 545.

[0762] [12] The reaction mixture was stirred at ambient temperature for2 hours. The reaction product was treated with 6M hydrogen chloride indiethyl ether to give the dihydrochloride salt. A portion thereof wastreated with a saturated methanolic ammonia solution, the mixture wasfiltered and the filtrate evaporated to give the free base which gavethe following data: NMR Spectrum: (CDCl₃) 1.8 (m, 4H), 2.0-2.2 (m, 4H),2.22 (d, 2H), 2.45-2.6 (m, 4H), 2.68 (m, 2H), 3.6 (m, 2H), 3.85 (s, 3H),4.05 (m, 2H), 4.15 (m, 2H), 4.78 (m, 1H), 6.55 (d, 1H), 6.65 (m, 1H),6.85 (d, 1H), 7.5 (d, 1H), 7.95 (d, 1H), 8.55 (s, 1H), 9.7 (s, 1H); MassSpectrum: M+H⁺ 557 and 559.

[0763] [13] The reaction mixture was stirred at ambient temperature for2 hours. The reaction product was treated with 6M hydrogen chloride indiethyl ether to give the dihydrochloride salt. A portion thereof wastreated with a saturated methanolic ammonia solution, the mixture wasfiltered and the filtrate evaporated to give the free base which gavethe following data: NMR Spectrum: (CDCl₃) 1.63 (br s, 6H), 2.0-2.2 (m,2H), 2.25 (d, 2H), 2.55 (br s, 4H), 2.85 (t, 2H), 3.6 (m, 2H), 3.84 (s,3H), 4.05 (m, 2H), 4.25 (m, 2H), 4.75 (m, 1H), 6.62 (m, 2H), 6.85 (d,1H), 7.5 (d, 1H), 7.95 (d, 1H), 8.55 (s, 1H), 9.7 (s, 1H); MassSpectrum: M+H⁺ 557 and 559.

[0764] [14] The reaction mixture was stirred at ambient temperature for2 hours. The reaction product was treated with 6M hydrogen chloride indiethyl ether to give the dihydrochlolide salt. A portion thereof wastreated with a saturated methanolic ammonia solution, the mixture wasfiltered and the filtrate evaporated to give the free base which gavethe following data: NMR Spectrum: (CDCl₃) 2.0-2.18 (m, 2H), 2.25 (d,2H), 2.31 (s, 3H), 2.5 (br s, 4H), 2.65 (br s, 4H), 2.9 (t, 2H), 3.6 (m,2H), 3.84 (s, 3H), 4.05 (m, 2H), 4.25 (t, 2H), 4.75 (m, 1H), 6.62 (m,2H), 6.85 (d, 1H), 7.5 (d, 1H), 7.95 (d, 1H), 8.55 (s, 1H), 9.7 (s, 1H);Mass Spectrum: M+H⁺ 572 and 574.

[0765] [15] The reaction mixture was stirred at ambient temperature for2 hours. The reaction product was treated with 6M hydrogen chloride indiethyl ether to give the dihydrochloride salt. A portion thereof wastreated with a saturated methanolic ammonia solution, the mixture wasfiltered and the filtrate evaporated to give the free base which gavethe following data: NMR Spectrum: (CDCl₃) 2.02-2.2 (m, 4H), 2.25 (d,2H), 2.29 (s, 3H), 2.35-2.7 (m, 10H), 3.6 (m, 2H), 3.84 (s, 3H), 4.1 (m,2H), 4.15 (t, 2H), 4.75 (m, 1H), 6.55 (s, 1H), 6.65 (m, 1H), 6.85 (d,1H), 7.5 (d, 1H), 7.95 (d, 1H), 8.55 (s, 1H), 9.7 (s, 1H); MassSpectrum: M+H⁺ 586 and 588.

[0766] [16] The reaction mixture was stirred at ambient temperature for2 hours. The reaction product was treated with 6M hydrogen chloride indiethyl ether to give the dihydrochloride salt. A portion thereof wastreated with a saturated methanolic ammonia solution, the mixture wasfiltered and the filtrate evaporated to give the free base which gavethe following data: NMR Spectrum: (CDCl₃) 2.0-2.2 (m, 2H), 2.22 (d, 2H),2.3 (s, 3H), 2.45 (br s, 4H), 3.6 (t, 2H), 3.65 (br s, 6H), 3.85 (s,3H), 4.05 (m, 2H), 4.42 (m, 2H), 4.45 (m, 2H), 4.75 (m, 1H), 6.48 (s,1H), 6.65 (m, 1H), 6.7 (s, 1H), 6.82 (d, 1H), 7.5 (d, 1H), 7.92 (d, 1H),8.55 (s, 1H), 9.68 (s, 1H); Mass Spectrum: M+H⁺ 653 and 655.

[0767] The 1-(2-hydroxyethyl)-5-methyl-2-morpholinomethylimidazole usedas a starting material was prepared as follows:

[0768] A mixture of 4-methyl-1-tritylimidazole (J. Heterocyclic Chem.,1982, 19, 253; 32.5 g), methyl bromoacetate (11.4 ml) and acetone (500ml) was heated to reflux for 2 hours. The solvent was removed byevaporation and the residue was dissolved in methanol (100 ml) andheated to reflux for 45 minutes. The mixture was evaporated and theresidue was triturated under diethyl ether. The resultant precipitatewas isolated and stirred at ambient temperature for 1 hour in a mixtureof diethyl ether (200 ml) and a saturated methanolic ammonia solution(20 ml). The mixture was filtered and the filtrate was evaporated. Theresidue was purified by column chromatography on silica using a 49:1mixture of methylene chloride and methanol as eluent. There was thusobtained methyl 2-(5-methylimidazol-1-yl)acetate (6 g); NMR Spectrum:(CDCl₃) 2.16 (s, 3H), 3.78 (s, 3H), 4.61 (s, 3H), 6.8 (s, 1H), 7.42 (s,1H).

[0769] A solution of a portion (1.7 g) of the material so obtained indiethyl ether (20 ml) was added dropwise to a stirred suspension oflithium aluminium hydride (0.76 g) in diethyl ether (70 ml) which wascooled to 0°C. The resultant mixture was stirred at ambient temperaturefor 1 hour. The mixture was cooled to 0°C. and a 6N aqueous sodiumhydroxide solution (0.8 ml) and water (2.4 ml) were added dropwise inturn. The mixture was stirred at ambient temperature for 30 minutes andthen evaporated. The residue was dissolved in methylene chloride, driedover magnesium sulphate and evaporated to give1-(2-hydroxyethyl)-5-methylimidazole (1.1 g); NMR Spectrum: (CDCl₃) 2.17(s, 3H), 3.81 (t, 2H), 3.92 (t, 2H), 6.6 (s, 1H), 7.24 (s, 1H).

[0770] Tert-butyldimethylsilyl chloride (9.05 g) was added to a stirredmixture of 1-(2-hydroxyethyl)-5-methylimidazole (6.4 g), imidazole (7.5g) and methylene chloride (30 ml) which was cooled to 0°C. The reactionmixture was stirred at ambient temperature for 4 hours. The mixture waspoured into water. The organic layer was washed with brine, dried overmagnesium sulphate and evaporated to give1-(2-tert-butyldimethylsilyloxyethyl)-5-methylimidazole (11.7 g); NMRSpectrum: (CDCl₃) -0.04 (s, 6H), 0.85 (s, 6H), 2.2 (s, 3H), 3.8 (m, 2H),3.94 (m, 2H), 6.75 (s, 1H), 7.43 (s, 1H).

[0771] The material so obtained was dissolved in THF (400 ml) and thesolution was cooled at −60° C. n-Butyllithium (2.5M in hexane, 40 ml)was added dropwise and the mixture was stirred at −50° C. for 1 hour.The mixture was cooled to −60° C. and DMF (12.5 ml) was added dropwise.The resultant mixture was allowed to warm to ambient temperature and wasstirred for 2 hours. Diethyl ether (500 ml) was added and the reactionmixture was poured into a saturated aqueous ammonium chloride solution.The organic layer was separated, washed with brine, dried over magnesiumsulphate and evaporated. The material so obtained was purified by columnchromatography on silica using increasingly polar mixtures of methylenechloride and a saturated methanolic ammonia solution as eluent. Therewas thus obtained1-(2-tert-butyldimethylsilyloxyethyl)-2-formyl-5-methylimidazole (11 g);NMR Spectrum: (CDCl₃) 0.1 (s, 6H), 0.79 (s, 9H), 2.32 (s, 3H), 3.91 (t,2H), 4.4 (t, 2H), 7.07 (s, 1H), 9.71 (s, 1H).

[0772] A portion (0.79 g) of the material so obtained was dissolved inmethylene chloride (24 ml) and morpholine (0.263 ml) and acetic acid(0.175 ml) were added. Sodium borohydride triacetate (0.8 g) was addedportionwise and the mixture was stirred at ambient temperature for 16hours. The mixture was evaporated and the residue was purified by columnchromatography on silica using a 49:1 mixture of methylene chloride anda saturated methanolic ammonia solution as eluent. There was thusobtained1-(2-tert-butyldimethylsilyloxyethyl)-5-methyl-2-morpholinomethylimidazole(0.5 g); NMR Spectrum: (CDCl₃) 0 (s, 6H), 0.82 (s, 9H), 2.25 (s, 3H),2.45 (m, 4H), 3.6 (s, 2H), 3.68 (m, 4H), 3.85 (t, 2H), 4.1 (t, 2H), 6.7(s, 1H).

[0773] A mixture of the material so obtained, 12N aqueous hydrochloricacid (0.26 ml) and methanol (10 ml) was stirred at ambient temperaturefor 5 hours. The mixture was evaporated and the residue was trituratedunder pentane. The resultant solid was isolated and dried under vacuum.The solid was stirred at ambient temperature for 1 hour in a mixture ofmethylene chloride and a saturated methanolic ammonia solution. Themixture was filtered and the filtrate was evaporated. The residue waspurified by column chromatography on silica using a 19:1 mixture ofmethylene chloride and a saturated methanolic ammonia solution aseluent. There was thus obtained1-(2-hydroxyethyl)-5-methyl-2-morpholinomethylimidazole (0.25 g); NMRSpectrum: (CDCl₃) 2.2 (s, 3H), 2.6 (br s, 4H), 3.58 (s, 2H), 3.7 (m,4H), 3.85 (t, 2H), 4.1 (t, 2H), 6.5-6.9 (br s, 1H), 6.65 (s, 1H).

[0774] [17] The reaction mixture was stirred at ambient temperature for2 hours. The reaction product was treated with 6M hydrogen chloride indiethyl ether to give the dihydrochloride salt. A portion thereof wastreated with a saturated methanolic ammonia solution, the mixture wasfiltered and the filtrate evaporated to give the free base which gavethe following data: NMR Spectrum: (CDCl₃) 1.75-2.3 (m, 8H), 2.5 (m, 1H),2.8-2.9 (m, 1H), 2.9 (s, 3H), 3.1 (s, 3H), 3.18 (m, 1H), 3.35 (m, 1H),3.48 (m, 1H), 3.58 (m, 2H), 3.82 (s, 3H), 4.05 (m, 2H), 4.2 (m, 2H),4.72 (m, 1H), 6.6 (m, 2H), 6.8 (s, 1H), 7.5 (d, 1H), 7.92 (d, 1H), 8.5(s, 1H), 9.68 (s, 1H); Mass Spectrum: M+H⁺ 614 and 616.

[0775] The (2S)-1-(2-hydroxyethyl)-N,N-dimethylpyrrolidine-2-carboxamideused as a starting material was prepared as follows:

[0776] A mixture of 1-(tert-butoxycarbonyl)-L-proline (10.75 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.6 g),dimethylamine hydrochloride (5.33 g), 4-dimethylaminopyridine (6.1 g)and methylene chloride (200 ml) was stirred at ambient temperature for 4hours. The mixture was poured into water. The organic layer wasseparated, washed in turn with a 1N aqueous potassium hydrogen sulphatesolution, with a 5% aqueous sodium bicarbonate solution and brine, driedover magnesium sulphate and evaporated to give1-(tert-butoxycarbonyl)-N,N-dimethyl-L-prolinamide (11.2 g); NMRSpectrum: (CDCl₃) 1.4 and 1.5 (2 s, 9H), 1.8-1.9 (m, 2H), 1.95-2.2 (m,2H), 3.0 and 3.1 (2 d, 6H), 3.35-3.6 (m, 2H), 4.55 and 4.7 (2 m, 1H).

[0777] A mixture of a portion (0.24 g) of the material so obtained andtrifluoroacetic acid (3 ml) was stirred at ambient temperature for 2hours. The mixture was evaporated and the residue was triturated underdiethyl ether. A slight excess of a 2M solution of hydrogen chloride indiethyl ether was added and the precipitate was isolated and dried undervacuum to give N,N-dimethyl-L-prolinamide hydrochloride salt (0.25 g);NMR Spectrum: (DMSOd₆ and CF₃CO₂D,) 1.7-2.0 (m, 3H), 2.3-2.5 (m, 1H),2.95 (s, 3H), 3.05 (s, 3H), 3.1-3.4 (m, 2H), 4.6 (m, 1H).

[0778] A mixture of N,N-dimethyl-L-prolinamide hydrochloride salt (6.3g), 2-bromoethanol (3.8 ml), potassium carbonate (14 g) and acetonitrile(70 ml) was stirred and heated to reflux for 16 hours. The mixture wasfiltered and the filtrate was evaporated. The residue was purified bycolumn chromatography on silica using a 24:1 mixture of methylenechloride and a saturated methanolic ammonia solution as eluent. Therewas thus obtained(2S)-1-(2-hydroxyethyl)-N,N-dimethylpyrrolidine-2-carboxamide (3.4 g);NMR Spectrum: (CDCl₃) 1.6 (m, 1H), 1.6-2.0 (m, 4H), 2.1-2.3 (m, 2H), 2.4(m, 1H), 2.9 (m, 1H), 3.0 (s, 3H), 3.05 (s, 3H), 3.25-3.4 (m, 2H), 3.75(m, 1H), 3.9 (m, 1H), 5.1 (br s, 1H); Mass Spectrum: M+H⁺ 187.

[0779] [18] The reaction mixture was stirred at ambient temperature for2 hours. The reaction product was treated with 6M hydrogen chloride indiethyl ether to give the dihydrochloride salt. A portion thereof wastreated with a saturated methanolic ammonia solution, the mixture wasfiltered and the filtrate evaporated to give the free base which gavethe following data: NMR Spectrum: (CDCl₃) 1.7-2.5 (m, 12H), 2.95 (s,3H), 3.1 (s, 3H), 2.8-3.0 (m, 1H ), 3.2-3.4 (m, 2H), 3.58 (t, 2H), 3.82(s, 3H), 4.05 (m, 2H), 4.1 (t, 2H), 4.75 (m, 1H), 6.55 (d, 1H), 6.6 (m,1H), 6.8 (d, 1H), 7.48 (d, 1H), 7.92 (d, 1H), 8.5 (s, 1H), 9.65 (s, 1H);Mass Spectrum: M+H⁺ 628 and 630.

[0780] The(2S)-1-(3-hydroxypropyl)-N,N-dimethylpyrrolidine-2-carboxamide used as astarting material was prepared as follows using an analogous procedureto that described in International Patent Application WO 98/13354(Example 76 thereof):

[0781] Using an analogous procedure to that described in the lastparagraph of the portion of Note [17] immediately above that isconcerned with the preparation of starting materials, 3-bromopropanolwas reacted with N,N-dimethyl-L-prolinamide hydrochloride salt.

[0782] [19] The reaction mixture was stirred at ambient temperature for2 hours. The reaction product was treated with 6M hydrogen chloride indiethyl ether to give the dihydrochloride salt. A portion thereof wastreated with a saturated methanolic ammonia solution, the mixture wasfiltered and the filtrate evaporated to give the free base which gavethe following data: NMR Spectrum: (CDCl₃) 1.6-1.8 (m, 2H), 1.9-2.0 (m,2H), 2.05-2.15 (m, 2H), 2.25 (d, 2H), 3.21 (m, 2H), 3.25-3.5 (m, 6H),3.33 (s, 3H), 3.34 (s, 3H), 3.58 (m, 2H), 3.84 (s, 3H), 4.05 (m, 2H),4.25 (m, 2H), 4.75 (m, 1H), 6.6 (d, 1H), 6.65 (m, 1H), 6.9 (d, 1H), 7.5(d, 1H), 7.95 (d, 1H), 8.55 (s, 1H), 9.7 (s, 1H); Mass Spectrum: M+H⁺631 and 633.

[0783] The (2R,5R)-1-(2-hydroxyethyl)-2,5-dimethoxymethylpyrrolidineused as a starting material was prepared as follows:

[0784] A mixture of (2R,5R)-2,5-dimethoxymethylpyrrolidine (0.25 g),2-bromoethanol (1.1 ml), potassium carbonate (2.8 g) and acetonitrile(10 ml) was stirred and heated to reflux for 18 hours. The mixture wasfiltered and the filtrate was poured on a column of silica and eluted bya 49:1 mixture of methylene chloride and a saturated methanolic ammoniasolution. There was thus obtained(2R,5R)-1-(2-hydroxyethyl)-2,5-dimethoxymethylpyrrolidine (0.23 g); MassSpectrum: M⁺H⁺ 204.

[0785] [20] 4-(2-Hydroxyethoxy)pyridine (J. Chem. Soc. Perkin II, 1987,1867) was used as a starting material. The product gave the followingdata: NMR Spectrum: (DMSOd₆) 1.65-1.9 (m, 2H), 2.25 (d, 2H), 3.55 (m,2H), 3.78 (s, 3H), 3.9 (m, 2H), 4.4-4.55 (m, 4H), 5.1 (m, 1H), 6.78 (m,1H), 6.85 (d, 1H), 7.0 (d, 1H), 7.05 (d, 2H), 7.6 (d, 1H), 7.84 (d, 1H),8.4 (d, 2H), 8.45 (s, 1H), 9.69 (s, 1H); Mass Spectrum: M+H⁺ 567 and569.

[0786] [21] The reaction mixture was stirred at ambient temperature for2 hours. The reaction product, obtained as the free base, gave thefollowing data: NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 1.2-1.35 (m, 1H),1.4-1.5 (m, 2H), 1.6 (m, 1H), 1.7-1.8 (m, 4H), 2.1-2.15 (m, 2H), 2.2-2.3(m, 2H), 3.1-3.2 (t, 2H), 3.35 (t, 2H), 3.55 (d, 2H), 3.7 (t, 2H), 3.8(s, 3H), 4.05 (d, 2H), 4.3 (t, 2H), 4.92 (m, 1H), 6.9 (s, 1H), 7.02 (d,1H), 7.05 (s, 1H), 7.58 (d, 1H), 7.58 (s, 1H), 7.9 (s, 1H); MassSpectrum: M+H⁺ 527 and 529.

[0787] The4-(2-chloro-5-methoxyanilino)-5-cyclohexyloxy-7-hydroxyquinazoline usedas a starting material was prepared as follows:

[0788] Using an analogous procedure to that described in Example 1,7-benzyloxy-4-(2-chloro-5-methoxyanilino)-5-hydroxyquinazoline (0.53 g)was reacted with cyclohexanol to give7-benzyloxy-4-(2-chloro-5-methoxyanilino)-5-cyclohexyloxyquinazoline(0.25 g); NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 1.3-1.4 (m, 1H), 1.4-1.55(m, 2H), 1.55-1.65 (m, 1H), 1.7-1.85 (m, 4H), 2.15 (m, 2H), 3.82 (s,3H), 4.95 (m, 1H), 5.4 (s, 2H), 7.0 (d, 1H), 7.05 (m, 1H), 7.2 (s, 1H),7.4-7.65 (m, 7H), 8.9 (s, 1H); Mass Spectrum: M+H⁺ 490 and 492.

[0789] Using an analogous procedure to that described in Example 20,7-benzyloxy-4-(2-chloro-5-methoxyanilino)-5-cyclohexyloxyquinazoline wasreacted with trifluoroacetic acid to give4-(2-chloro-5-methoxyanilino)-5-cyclohexyloxy-7-hydroxyquinazoline; NMRSpectrum: (DMSOd₆ and CF₃CO₂D) 1.2-1.35 (m, 1H), 1.4-1.55 (m, 2H),1.55-1.65 (m, 1H), 1.7-1.85 (m, 4H), 2.15 (m, 2H), 3.82 (s, 3H), 4.85(m, 1H), 6.8 (s, 1H), 7.0 (s, 1H), 7.05 (m, 1H), 7.55 (d, 1H), 7.6 (d,1H), 8.82 (s, 1H); Mass Spectrum: M+H⁺ 400 and 402.

[0790] [22] The reaction mixture was stirred at ambient temperature for2 hours. The reaction product, obtained as the free base, gave thefollowing data: NMR Spectrum: (CDCl₃) 1.65-1.75 (m, 2H), 1.75-1.8 (m,2H), 1.8-1.9 (m, 4H), 2.05-2.18 (m, 4H), 2.65 (m, 4H), 2.98 (m, 2H),3.95 (s, 3H), 4.22 (m, 2H), 5.02 (m, 1H), 6.62 (d, 1H), 6.85 (d, 1H),7.4 (s, 1H), 8.38 (s, 1H), 8.55 (s, 1H), 9.8 (s, 1H); Mass Spectrum:M+H⁺ 517 and 519.

[0791] The5-cyclopentyloxy-4-(2,4-dichloro-5-methoxyanilino)-7-hydroxyquinazolineused as a starting material was prepared as follows:

[0792] Di-tert-butyl azodicarboxylate (1.1 g) was added portionwise to astirred mixture 5-hydroxy-7-methoxy-3,4-dihydroquinazolin-4-one (1 g),cyclopentanol (0.385 ml), triphenylphosphine (1.28 g) and methylenechloride (16 ml) which was maintained at ambient temperature using awater bath. The mixture was stirred at ambient temperature for 1 hour. A6M solution of hydrogen chloride in diethyl ether (4 ml) was added andthe mixture was stirred at ambient temperature for 10 minutes. Theresultant precipitate was isolated, washed with methylene chloride andwith ethyl acetate and dried under vacuum. The product so obtained wasstirred in methanol (16 ml) containing sodium hydroxide (0.28 g) atambient temperature for 1 hour. The mixture was evaporated and the solidwas triturated under water (20 ml) containing acetic acid (1 ml). Theresultant precipitate was isolated, washed in turn with water, ethylacetate and diethyl ether. There was thus obtained5-cyclopentyloxy-7-methoxy-3,4-dihydroquinazoline-4-one (0.52 g); NMRSpectrum: (CDCl₃) 1.55 (br s, 2H), 1.75 (m, 4H), 1.9 (m, 2H), 3.85 (s,3H), 4.9 (br s, 1H), 6.5 (s, 1H), 6.62 (s, 1H), 7.9 (s, 1H), 11.62 (brs, 1H); Mass Spectrum: M+H⁺ 261.5.

[0793] The material so obtained was mixed with potassium carbonate(0.414 g) and N-methylpyrrolidin-2-one (10 ml) and thiophenol (0.306 ml)was added. The resultant mixture was stirred and heated to 175° C. for30 minutes. The mixture was evaporated and the residue was poured intowater (20 ml) containing acetic acid (1 ml). The resultant precipitatewas isolated, washed with ethyl acetate and dried under vacuum to give5-cyclopentyloxy-7-hydroxy-3,4-dihydroquinazolin-4-one (0.4 g); NMRSpectrum: (DMSOd₆) 1.6 (m, 2H), 1.8 (m, 4H), 1.9 (m, 2H), 4.8 (br s,1H), 6.38 (s, 1H), 6.5 (s, 1H), 7.8 (s, 1H), 10.35 (s, 1H), 11.5 (br s,1H); Mass Spectrum: M+H⁺ 247.5.

[0794] A mixture of5-cyclopentyloxy-7-hydroxy-3,4-dihydroquinazolin-4-one (13 g), aceticanhydride (25 ml) and pyridine (21 ml) was stirred and heated to 100° C.for 1 hour. The mixture was evaporated and the residue was dissolved ina mixture of water (70 ml) and methanol (70 ml) and stirred at 15° C.for 30 minutes. The methanol was evaporated and the resultantprecipitate was isolated, washed with water and dried under vacuum togive 7-acetoxy-5-cyclopentyloxy-3,4-dihydroquinazolin-4-one (12.2 g);NMR Spectrum: (DMSOd₆) 1.6 (br s, 2H), 1.8 (m, 4H), 1.92 (m, 2H), 2.3(s, 3H), 4.9 (m, 1H), 6.8 (s, 1H), 6.9 (s, 1H), 7.95 (s, 1H), 11.9 (brs, 1H); Mass Spectrum: M+H⁺ 289.6.

[0795] Using an analogous procedure to that described in the lastparagraph of Note [9] in Example 15,7-acetoxy-5-cyclopentyloxy-3,4-dihydroquinazolin-4-one (5 g) was reactedwith carbon tetrachloride and triphenylphosphine to give7-acetoxy-4-chloro-5-cyclopentyloxyquinazoline (5.3 g); NMR Spectrum:(CDCl₃) 1.65-1.8 (m, 2H), 1.8-2.05 (m, 4H), 2.1 (m, 2H), 2.4 (s, 3H),4.95 (m, 1H), 6.78 (d, 1H), 7.35 (d, 1H), 8.9 (s, 1H); Mass Spectrum:M+H⁺ 307 and 309.

[0796] A mixture of a portion (1 g) of the material so obtained,2,4-dichloro-5-methoxyaniline hydrochloride (0.82 g), triethylamine(0.408 ml) and isopropanol (6 ml) was stirred and heated to 80° C. for1.5 hours. The precipitate was isolated, washed in turn withisopropanol, ethyl acetate and diethyl ether and dried under vacuum togive7-acetoxy-5-cyclopentyloxy-4-(2,4-dichloro-5-methoxyanilino)quinazoline(1.2 g); NMR Spectrum: (DMSOd₆) 1.6-1.8 (m, 4H), 1.95-2.2 (m, 4H), 2.4(s, 3H), 3.9 (s, 3H), 5.25 (br s, 1H), 7.3 (s, 2H), 7.82 (s, 1H), 7.9(s, 1H), 8.82 (s, 1H), 10.32 (s, 1H); Mass Spectrum: M+H⁺ 462 and 464.

[0797] A mixture of the material so obtained and a saturated methanolicammonia solution (20 ml) was stirred at ambient temperature for 4 hours.The mixture was evaporated and the residue was triturated under water.The resultant solid was isolated and dried under vacuum to give5-cyclopentyloxy-4-(2,4-dichloro-5-methoxyanilino)-7-hydroxyquinazoline(1 g); NMR Spectrum: (DMSOd₆) 1.6-1.8 (m, 4H), 1.95 (m, 2H), 2.0-2.15(m, 2H), 3.9 (s, 3H), 5.15 (m, 1H), 6.7 (s, 2H), 7.7 (s, 1H), 8.3 (s,1H), 8.4 (s, 1H), 9.7 (s, 1H), 10.5-10.7 (br s, 1H); Mass Spectrum: M+H⁺420 and 422.

[0798] [23] The free base product gave the following data: NM Spectrum:(DMSOd₆ and CF₃CO₂D) 1.5 (d, 6H), 2.2-2.3 (m, 2H), 3.15 (t, 2H), 3.3-3.4(m, 2H), 3.52 (d, 2H), 3.7 (m, 2H), 3.8 (s, 3H), 4.02 (d, 2H), 4.3 (t,2H), 5.1-5.2 (m, 1H), 6.9 (s, 1H), 7.0 (m, 2H), 7.55 (d, 1H), 7.65 (s,1H), 8.9 (s, 1H); Mass Spectrum: M+H⁺ 487 and 489.

[0799] [24] The free base product gave the following data: NM Spectrum:(DMSOd₆) 1.5 (d, 6H), 1.95 (m, 2H), 2.18 (s, 3H), 2.2-2.6 (m, 10H), 3.8(s, 3H), 4.2 (t, 2H), 5.1 (m, 1H), 6.75-6.85 (m, 3H), 7.48 (d, 1H), 8.2(s, 1H), 8.5 (s, 1H), 10.0 (s, 1H); Mass Spectrum: M+H³⁰ 500 and 502.

[0800] [25] The reaction mixture was stirred at ambient temperature for2 hours. The free base product gave the following data: NMR Spectrum:(DMSOd₆) 1.7 (br s, 4H), 1.8-1.95 (m, 2H), 2.15 (d, 2H), 2.55 (br s,4H), 2.85 (m, 2H), 3.55 (m, 2H), 3.95 (m, 2H), 4.22 (m, 2H), 5.05 (m,1H), 6.15 (s, 2H), 6.75 (d, 1H), 6.85 (d, 1H), 6.9-7.0 (m, 2H), 8.1 (d,1H), 8.5 (s, 1H), 9.85 (s, 1H); Mass Spectrum: M+H⁺ 479.

[0801] The4-(2,3-methylenedioxyanilino)-7-hydroxy-5-tetrahydropyran-4-yloxyquinazolineused as a starting material was prepared as follows:

[0802] A mixture of7-acetoxy-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (3.04g), diisopropylethylamine (4.34 ml), phosphoryl chloride (1.02 ml) and1,2-dichloroethane (60 ml) was stirred and heated to 80° C. for 2 hours.The mixture was evaporated to give7-acetoxy-4-chloro-5-tetrahydropyran-4-yloxyquinazoline which was usedwithout further purification.

[0803] A mixture of the material so obtained, 2,3-methylenedioxyaniline(1.5 g) and isopropanol (20ml) was stirred and heated to 80° C. for 1hour. The mixture was cooled to ambient temperature and the resultantsolid was isolated, washed in turn with isopropanol and diethyl etherand dried under vacuum. There was thus obtained7-acetoxy-4-(2,3-methylenedioxyanilino)-5-tetrahydropyran-4-yloxyquinazolinehydrochloride (3.6 g); NMR Spectrum: (DMSOd₆) 1.9-2.05 (m, 2H), 2.1-2.25(m, 2H), 2.4 (s, 3H), 3.55 (m, 2H), 3.98 (m, 2H), 5.1 (m, 1H), 6.2 (s,2H), 6.95-7.05 (m, 2H), 7.32 (s, 1H), 7.5 (s, 1H), 7.62 (m, 1H), 9.0 (s,1H); Mass Spectrum: M+H⁺424.

[0804] Using an analogous procedure to that described in the lastparagraph of Note [22] immediately above,7-acetoxy-4-(2,3-methylenedioxyanilino)-5-tetrahydropyran-4-yloxyquinazolinewas reacted with a saturated methanolic ammonia solution to give4-(2,3-methylenedioxyanilino)-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline;NMR Spectrum: (DMSOd₆) 1.8-1.95 (m, 2H), 2.1-2.2 (m, 2H), 3.52 (m, 2H),3.8 (s, 3H), 3.9 (m, 2H), 4.95 (m, 1H), 6.7 (s, 1H), 6.75 (d, 1H), 6.85(s, 1H), 7.6 (d, 1H), 7.88 (s, 1H), 8.4 (s, 1H), 9.65 (s, 1H), 10.6 (brs, 1H); Mass Spectrum: M+H⁺ 382.

[0805] [26] The reaction mixture was stirred at ambient temperature for2 hours. The free base product gave the following data: NMR Spectrum:(DMSOd₆) 1.7 (br s, 4H), 1.75-1.9 (m, 2H), 1.9-2.0 (m, 2H), 2.15 (d,2H), 2.5 (br s, 4H), 2.6 (m, 2H), 3.55 (m, 2H), 3.9 (m, 2H), 4.18 (m,2H), 5.0 (m, 1H), 6.1 (s, 2H), 6.72 (d, 1H), 6.8 (s, 1H), 6.9 (m, 2H),8.08 (d, 1H), 8.5 (s, 1H), 8.82 (s, 1H); Mass Spectrum: M+H⁺ 493.

[0806] [27] The reaction mixture was stirred at ambient temperature for2 hours. The reaction product was treated with 6M hydrogen chloride inisopropanol to give4-(2-bromo-5-methoxyanilino)-5-piperidin-4-yloxy-7-(3-pyridylmethoxy)quinazolinedihydrochloride, a portion of which was converted to the free base usingan analogous procedure to that described in Example 3. The free basegave the following data: NMR Spectrum: (CDCl₃) 1.85-2.0 (m, 2H), 2.25(d, 2H), 2.78 (m, 2H), 3.2 (m, 2H), 3.85 (s, 3H), 4.65 (m, 1H), 5.2 (s,2H), 6.62 (s, 1H), 6.65 (m, 1H), 6.92 (d, 1H), 7.38 (m, 1H ), 7.5 (d,1H), 7.82 (d, 1H), 7.92 (d, 1H), 8.55 (s, 1H), 8.65 (d, 1H), 8.75 (s,1H), 9.72 (s, 1H); Mass Spectrum: M+H⁺ 536 and 538.

[0807] [28] The reaction mixture was stirred at ambient temperature for2 hours. The reaction product gave the following data: NMR Spectrum:(CDCl₃) 1.8-1.9 (m, 4H), 1.95-2.1 (m, 2H), 2.12 (d, 2H), 2.68 (br s,4H), 3.0 (t, 2H), 3.58 (t, 2H), 3.98 (s, 3H), 4.08 (m, 2H), 4.25 (t,2H), 4.72 (m, 1H), 6.8 (d, 1H), 6.9 (d, 1H), 7.42 (s, 1H), 8.4 (s, 1H),8.6 (s, 1H), 9.9 (s, 1H); Mass Spectrum: M+H⁺ 533 and 535.

[0808] The4-(2,4-dichloro-5-methoxyanilino)-7-hydroxy-5-tetrahydropyran-4-yloxyquinazolineused as a starting material was prepared as follows:

[0809] A mixture of7-acetoxy-4-chloro-5-tetrahydropyran-4-yloxyquinazoline (prepared from7-acetoxy-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (3.04 g)and phosphoryl chloride), 2,4-dichloro-5-methoxyaniline (2.1 g) andisopropanol (20ml) was stirred and heated to 80° C. for 1 hour. Themixture was cooled to ambient temperature and the resultant solid wasisolated, washed in turn with isopropanol and diethyl ether and driedunder vacuum. There was thus obtained7-acetoxy-4-(2,4-dichloro-5-methoxyanilino)-5-tetrahydropyran-4-yloxyquinazolinehydrochloride (3.5 g); NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 1.9-2.1 (m,2H), 2.15 (d, 2H), 2.4 (s, 3H), 3.52 (t, 2H), 3.9 (s, 3H), 3.95 (m, 2H),5.1 (m, 1H), 7.4 (d, 1H), 7.55 (d, 1H), 7.78 (s, 1H), 7.95 (s, 1H), 8.95(s, 1H); Mass Spectrum: M+H⁺ 478 and 480.

[0810] Using an analogous procedure to that described in the lastparagraph of Note

[0811] [22] immediately above,7-acetoxy-4-(2,4-dichloro-5-methoxyanilino)-5-tetrahydropyran-4-yloxyquinazolinewas reacted with a saturated methanolic ammonia solution to give4-(2,4-dichloro-5-methoxyanilino)-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline;NMR Spectrum: (DMSOd₆) 1.75-1.9 (m, 2H), 2.18 (d, 2H), 3.52 (t, 2H), 3.9(s, 3H), 3.95 (m, 2H), 4.95 (m, 1H), 6.7 (d, 1H), 6.82 (d, 1H), 7.7 (s,1H), 8.35 (s, 1H), 8.42 (s, 1H), 9.85 (s, 1H), 10.5-10.7 (br s, 1H);Mass Spectrum: M+H⁺ 436 and 438.

[0812] [29] The reaction mixture was stirred at ambient temperature for2 hours. The reaction product gave the following data: NMR Spectrum:(CDCl₃) 1.85 (br s, 4H), 2.0-2.15 (m, 4H), 2.25 (d, 2H), 2.6 (br s, 4H),2.68 (t, 2H), 3.6 (t, 2H), 3.96 (s, 3H), 4.08 (m, 2H), 4.18 (t, 2H),4.75 (m, 1H), 6.6 (d, 1H), 6.88 (d, 1H), 7.45 (s, 1H), 8.4 (s, 1H), 8.6(s, 1H); Mass Spectrum: M+H⁺ 547 and 549.

[0813] [30] The reaction mixture was stirred at ambient temperature for2 hours. The reaction product gave the following data: NMR Spectrum:(CDCl₃) 1.4-1.5 (m, 2H), 1.5-1.75 (m, 6H), 2.0-2.1 (m, 2H), 2.25 (d,2H), 2.52 (br s, 4H), 2.85 (t, 2H), 3.58 (m, 2H), 3.96 (s, 3H), 4.08 (m,2H), 4.25 (t, 2H), 4.75 (m, 1H), 6.65 (d, 1H), 6.68 (d, 1H), 7.25 (s,1H), 8.4 (s, 1H), 8.58 (s, 1H), 9.85 (s, 1H); Mass Spectrum: M+H⁺ 547and 549.

[0814] [31] The reaction mixture was stirred at ambient temperature for2 hours. The reaction product gave the following data: NMR Spectrum:(CDCl₃) 1.98-2.12 (m, 4H), 2.22 (d, 2H), 2.32 (s, 3H), 2.5 (br s, 2H),2.65 (br s, 2H), 2.9 (t, 2H), 3.6 (m, 2H), 3.96 (s, 3H), 4.08 (m, 2H),4.25 (t, 2H), 4.75 (m, 1H), 6.61 (d, 1H), 6.86 (d, 1H), 7.42 (s, 1H),8.4 (s, 1H), 8.6 (s, 1H), 9.85 (d, 1H); Mass Spectrum: M+H⁺ 562 and 564.

[0815] [32] The reaction mixture was stirred at ambient temperature for2 hours. The reaction product gave the following data: NMR Spectrum:(CDCl₃) 2.0-2.1 (m, 2H), 2.22 (d, 2H), 2.6 (m, 4H), 2.9 (t, 2H), 3.6 (m,2H), 3.8 (m, 4H), 3.98 (s, 3H), 4.08 (m, 2H), 4.25 (t, 2H), 4.75 (m,1H), 6.62 (d,1H), 6.88 (d, 1H), 7.42 (s, 1H), 8.4 (s, 1H), 8.6 (s, 1H),9.9 (s, 1H); Mass Spectrum: M+H⁺ 549 and 551.

[0816] [33] The reaction mixture was stirred at ambient temperature for3 hours. The reaction product gave the following data: Mass Spectrum:M+H⁺ 590 and 592.

[0817] The (2S)-1-(2-hydroxyethyl)-N-methylprolinamide used as astarting material was obtained as follows:

[0818] A mixture of 1-(tert-butoxycarbonyl)-L-proline (5.4 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (5.3 g), methylaminehydrochloride (2.2 g), 4-dimethylaminopyridine (3 g) and metlhylenechloride (50 ml) was stirred at ambient temperature for 16 hours. Theresultant mixture was poured in water and the organic layer wasseparated, washed in turn with a 1M aqueous potassium hydrogen sulphatesolution, a saturated aqueous sodium bicarbonate solution and brine,dried over magnesium sulphate and evaporated. There was thus obtained1-(tert-butoxycarbonyl)-N-methyl-L-prolinamide (5.6 g); Mass Spectrum:M+H⁺ 229.

[0819] A mixture of a portion (4.4 g) of the material so obtained andtrifluoroacetic acid (10 ml) was stirred at ambient temperature for 2hours. The mixture was evaporated and the residue was triturated underdiethyl ether. The resultant solid was isolated, washed with diethylether and dried under vacuum. There was thus obtained to giveN-methyl-L-prolinamide trifluoroacetic acid salt (3.7 g); NMR Spectrum:(DMSOd₆ and CF₃CO₂D) 1.85-2.05 (m, 3H), 2.2-2.3 (m, 1H), 2.73 (s, 3H),3.2-3.4 (m, 2H), 4.2 (m, 1H).

[0820] A mixture of a portion (2.5 g) of the material so obtained,2-bromoethanol (2.15 ml), potassium carbonate (5.5 g) and acetonitrile(20 ml) was stirred and heated to reflux for 18 hours. The mixture wascooled to ambient temperature, filtered and evaporated and the residuewas purified by column chromatography on silica using a 49:1 mixture ofmethylene chloride and a saturated methanolic ammonia solution aseluent. There was thus obtained(2S)-1-(2-hydroxyethyl)-N-methylprolinamide (0.5 g); NMR Spectrum:(CDCl₃) 1.6-2.0 (m, 4H), 2.1-2.3 (m, 1H), 2.3-2.45 (m, 1H), 2.6-2.7 (m,1H), 2.85 (d, 3H), 2.8-2.9 (m, 1H), 3.1-3.2 (m, 1H), 3.2-3.3 (m, 1H),3.6-3.8 (m, 2H); Mass Spectrum: M+H⁺ 173.

[0821] [34] The reaction mixture was stirred at ambient temperature for3 hours. The reaction product gave the following data: Mass Spectrum:M+H⁺ 576 and 578.

[0822] The (2S)-1-(2-hydroxyethyl)prolinamide used as a startingmaterial was prepared by the reaction of L-prolinamide and2-bromoethanol using an analogous procedure to that described in Note[33] immediately above. There was thus obtained the required startingmaterial; NMR Spectrum: (CDCl₃) 1.6-2.0 (m, 4H), 2.1-2.25 (m, 1H),2.35-2.45 (m, 1H), 2.6-2.7 (m, 1H), 2.8-3.0 (m, 1H), 3.1 (m, 1H),3.2-3.3 (m, 1H), 3.6-3.8 (m, 2H), 5.6 (br s, 1H), 7.4 (br s, 1H); MassSpectrum: M+H⁺ 159.

[0823] [35] The reaction mixture was stirred at ambient temperature for3 hours. The reaction product gave the following data: Mass Spectrum:M+H⁺ 646 and 648.

[0824] The (2S)-1-(2-hydroxyethyl)-2-morpholinocarbonylpyrrolidine usedas a starting material was prepared as follows:

[0825] Using analogous procedures to those described in Note [33]immediately above, 1-(tert-butoxycarbonyl)-L-proline was reacted withmorpholine to give(2S)-1-(tert-butoxycarbonyl)-2-morpholinocarbonylpyrrolidine which wasdeprotected and reacted with 2-bromoethanol. There was thus obtained therequired starting material; NMR Spectrum: (CDCl₃) 1.7-2.0 (m, 4H),2.1-2.2 (m, 1H), 2.4-2.5 (m, 1H), 2.6-2.7 (m, 1H), 2.8-2.9 (m, 1H),3.3-3.4 (m, 2H), 3.4-3.8 (m, 10H); Mass Spectrum: M+H⁺ 229.

[0826] [36] The reaction mixture was stirred at ambient temperature for3 hours. The reaction product gave the following data: Mass Spectrum:M+H⁺ 659 and 661.

[0827] The(2S)-1-(2-hydroxyethyl)-2-(4-methylpiperazin-1-ylcarbonyl)pyrrolidineused as a starting material was prepared as follows:

[0828] Using analogous procedures to those described in Note [33]immediately above, 1-(tert-butoxycarbonyl)-L-proline was reacted with1-methylpiperazine to give(2S)-1-(tert-butoxycarbonyl)-2-(4-methylpiperazin-1-ylcarbonyl)pyrrolidinewhich was deprotected and reacted with 2-bromoethanol. There was thusobtained the required starting material; NMR Spectrum: (CDCl₃) 1.7-2.05(m, 4H), 2.1-2.25 (m, 1H), 2.32 (s, 3H), 2.35-2.5 (m, 4H), 2.6-2.7 (m,1H), 2.8-2.9 (m, 1H), 3.3-3.7 (m, 8H), 4.15 (br s, 1H); Mass Spectrum:M+H⁺ 242.

[0829] [37] The reaction mixture was stirred at ambient temperature for3 hours. The reaction product gave the following data: Mass Spectrum:M+H⁺ 630 and 632.

[0830] The(2S)-1-(2-hydroxyethyl)-2-(pyrrolidin-1-ylcarbonyl)pyrrolidine used as astarting material was prepared as follows:

[0831] Using analogous procedures to those described in Note [33]immediately above, 1-(tert-butoxycarbonyl)-L-proline was reacted withpyrrolidine to give(2S)-1-(tert-butoxycarbonyl)-2-(pyrrolidin-1-ylcarbonyl)pyrrolidinewhich was deprotected and reacted with 2-bromoethanol. There was thusobtained the required starting material; NMR Spectrum: (CDCl₃) 1.7-2.05(m, 8H), 2.1-2.3 (m, 1H), 2.42.5 (m, 1H), 2.55-2.7 (m, 1H), 2.8-2.9 (m,1H), 3.2-3.3 (m, 2H), 3.4-3.7 (m, 5H), 4.1 (br s, 1H); Mass Spectrum:M+H⁺ 213.

[0832] [38] The reaction mixture was stirred at ambient temperature for3 hours. The reaction product gave the following data: Mass Spectrum:M+H⁺ 644 and 646.

[0833] The (2S)-1-(2-hydroxyethyl)-2-piperidinocarbonylpyrrolidine usedas a starting material was prepared as follows:

[0834] Using analogous procedures to those described in Note [33]immediately above, 1-(tert-butoxycarbonyl)-L-proline was reacted withpiperidine to give(2S)-1-(tert-butoxycarbonyl)-2-piperidinocarbonylpyrrolidine which wasdeprotected and reacted with 2-bromoethanol. There was thus obtained therequired starting material; NMR Spectrum: (CDCl₃) 1.5-1.9 (m, 10H),1.9-2.0 (m, 1H), 2.1-2.2 (m, 1H), 2.4-2.5 (m, 1H), 2.55-2.65 (m, 1H),2.8-2.9 (m, 1H), 3.3-3.7 (m, 6H), 4.3 (br s, 1H); Mass Spectrum: M+H⁺227.

[0835] [39] The reaction mixture was stirred at ambient temperature for3 hours. The reaction product gave the following data: Mass Spectrum:M+H⁺ 547 and 549.

[0836] The (2R)-1-(2-hydroxyethyl)-2-methylpyrrolidine used as astarting material was obtained as follows:

[0837] A mixture of (2R)-2-methylpyrrolidine (0.853 g), 2-bromoethanol(1.1 ml), potassium carbonate (2.8 g) and acetonitrile (10 ml) wasstirred and heated to reflux for 18 hours. The mixture was filtered andthe filtrate was evaporated. The resultant residue was purified bycolumn chromatography on silica using a 49:1 mixture of methylenechloride and a saturated methanolic ammonia solution as eluent. Therewas thus obtained (2R)-1-(2-hydroxyethyl)-2-methylpyrrolidine (0.35 g);NMR Spectrum: (CDCl₃) 1.1 (d, 3H), 1.3-1.5 (m, 1H), 1.6-1.8 (m, 3H),1.95 (m, 1H), 2.15 (m, 1H), 2.28 (m, 1H), 2.4-2.5 (m, 1H), 2.95-3.05 (m,1H), 3.2 (m, 1H), 3.5-3.8 (m, 2H); Mass Spectrum: M+H⁺ 130.

[0838] [40] The reaction mixture was stirred at ambient temperature for3 hours. The reaction product gave the following data: Mass Spectrum:M+H⁺ 577 and 579.

[0839] The (2S)-1-(2-hydroxyethyl)-2-methoxymethylpyrrolidine used as astarting material was obtained as follows:

[0840] Using an analogous procedure to those described in Note [39]immediately above, (2S)-2-methoxymethylpyrrolidine was reacted with2-bromoethanol to give(2S)-1-(2-hydroxyethyl)-2-methoxymethylpyrrolidine; NMR Spectrum:(CDCl₃) 1.5-1.65 (m, 1H), 1.65-1.8 (m, 2H), 1.8-2.0 (m, 2H), 2.3 (m,1H), 2.6 (m, 1H), 2.8 (m, 1H), 2.95-3.05 (m, 1H), 3.17 (m, 1H), 3.3 (t,1H, 3.35 (t, 1H), 3.37 (s, 3H), 3.5-3.7 (m, 2H).

[0841] [41] The reaction mixture was stirred at ambient temperature for3 hours. The reaction product gave the following data: Mass Spectrum:M+H⁺ 557 and 559.

[0842] [42] The reaction mixture was stirred at ambient temperature for3 hours. The reaction product gave the following data: Mass Spectrum:M+H⁺ 527 and 529.

[0843] [43] The reaction mixture was stirred at ambient temperature for3 hours. The reaction product gave the following data: Mass Spectrum:M+H⁺ 527 and 529.

[0844] [44] The reaction mixture was stirred at ambient temperature for3 hours. The reaction product gave the following data: Mass Spectrum:M+H⁺ 533 and 535.

[0845] [45] (2S)-1-(2-Hydroxyethyl)-N-methylprolinamide was used as astarting material and the reaction mixture was stirred at ambienttemperature for 3 hours. The reaction product gave the following data:Mass Spectrum: M+H⁺ 600 and 602.

[0846] [46] (2S)-1-(2-Hydroxyethyl)-2-morpholinocarbonylpyrrolidine wasused as a starting material and the reaction mixture was stirred atambient temperature for 3 hours. The reaction product gave the followingdata: Mass Spectrum: M+H⁺ 658 and 660.

[0847] [47](2S)-1-(2-Hydroxyethyl)-2-(4-methylpiperazin-1-ylcarbonyl)pyrrolidinewas used as a starting material and the reaction mixture was stirred atambient temperature for 3 hours. The reaction product gave the followingdata: Mass Spectrum: M+H⁺ 671 and 673.

[0848] [48](2S)-1-(2-Hydroxyethyl)-2-(pyrrolidin-1-ylcarbonyl)pyrrolidine was usedas a starting material and the reaction mixture was stirred at ambienttemperature for 3 hours. The reaction product gave the following data:Mass Spectrum: M+H⁺ 642 and 644.

[0849] [49] (2S)-1-(2-Hydroxyethyl)-2-piperidinocarbonylpyrrolidine wasused as a starting material and the reaction mixture was stirred atambient temperature for 3 hours. The reaction product gave the followingdata: Mass Spectrum: M+H⁺ 656 and 658.

[0850] [50] (2S)-1-(2-Hydroxyethyl)prolinamide was used as a startingmaterial and the reaction mixture was stirred at ambient temperature for3 hours. The reaction product gave the following data: Mass Spectrum:M+H⁺ 588 and 590.

[0851] [51] (2R)-1-(2-Hydroxyethyl)-2-methylpyrrolidine was used as astarting material and the reaction mixture was stirred at ambienttemperature for 3 hours. The reaction product gave the following data:Mass Spectrum: M+H⁺ 557 and 559.

[0852] [52] (2S)-1-(2-Hydroxyethyl)-2-methoxymethylpyrrolidine was usedas a starting material and the reaction mixture was stirred at ambienttemperature for 3 hours. The reaction product gave the following data:Mass Spectrum: M+H⁺ 587 and 589.

[0853] [53] The reaction mixture was stirred at ambient temperature for3 hours. The reaction product gave the following data: Mass Spectrum:M+H⁺ 537 and 539.

[0854] [54] The reaction mixture was stirred at ambient temperature for3 hours. The reaction product gave the following data: Mass Spectrum:M+H⁺ 537 and 539.

[0855] [55] The reactants were5-[N-(tert-butoxycarbonyl)piperidin-4-yloxy]-4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxyquinazolineand isopropanol. The reaction mixture was stirred at ambient temperaturefor 1 hour. Thereafter, a 6M solution of hydrogen chloride in diethylether was added and the reaction mixture was stirred at ambienttemperature for 1 hour. The resultant precipitate was isolated, washedwith ethyl acetate and diethyl ether and dried. There was thus obtainedthe required product,4-(6-chloro-2,3-methylenedioxyanilino)-7-isopropoxy-5-piperidin-4-yloxyquinazoline;NMR Spectrum: (CDCl₃) 1.4 (d, 6H), 1.8-1.9 (m, 2H), 2.25 (m, 2H),1.75-1.85 (m, 2H), 3.1-3.2 (m, 2H), 4.7 (m, 1H), 4.72 (m, 1H), 6.05 (s,2H), 6.5 (d, 1H), 6.7 (d, 1H), 6.82 (d, 1H), 6.98 (d, 1H), 8.5 (s, 1H),9.32 (s, 1H); Mass Spectrum: M+H⁺ 457 and 459.

[0856] The5-[N-(tert-butoxycarbonyl)piperidin-4-yloxy]4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxyquinazolineused as a starting material is described in Example 35 hereinafter.

[0857] [56] The reactants were5-[N-(tert-butoxycarbonyl)piperidin-4-yloxy]-4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxyquinazolineand ethanol. The reaction mixture was stirred at ambient temperature for1 hour. Thereafter, a 6M solution of hydrogen chloride in diethyl etherwas added and the reaction mixture was stirred at ambient temperaturefor 1 hour. The resultant precipitate was isolated, washed with ethylacetate and diethyl ether and dried. There was thus obtained therequired product,4(6-chloro-2,3-methylenedioxyanilino)-7-ethoxy-5-piperidin-4-yloxyquinazoline;NMR Spectrum: (CDCl₃) 1.45 (t, 3H), 1.7-1.9 (m, 2H), 2.1-2.25 (m, 2H),2.7-2.8 (m, 2H), 3.05-3.2 (m, 2H), 4.12 (q, 2H), 4.6 (m, 1H), 6.02 (s,2H), 6.48 (d, 1H), 6.7 (d, 1H), 6.8 (d, 1H), 6.92 (d, 1H), 8.5 (s, 1H),9.3 (s, 1H); Mass Spectrum: M+H⁺ 443 and 445.

[0858] [57] The reactants were5-[N-(tert-butoxycarbonyl)piperidin-4-yloxy]-4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxyquinazolineand isobutanol. The reaction mixture was stirred at ambient temperaturefor 1 hour. Thereafter, a 6M solution of hydrogen chloride in diethylether was added and the reaction mixture was stirred at ambienttemperature for 1 hour. The resultant precipitate was isolated, washedwith ethyl acetate and diethyl ether and dried. There was thus obtainedthe required product,4-(6-chloro-2,3-methylenedioxyanilino)-7-isobutoxy-5-piperidin-4-yloxyquinazoline;NMR Spectrum: (CDCl₃) 1.05 (d, 6H), 1.8-1.9 (m, 2H), 2.12 (m, 1H),2.2-2.3 (m, 2H, 2.75-2.9 (m, 2H), 3.1-3.2 (m, 2H), 4.85 (d, 2H), 4.65(m, 1H), 6.05 (s, 2H), 6.5 (d, 1H), 6.7 (d, 1H), 6.8 (d, 1H), 6.95 (d,1H), 8.5 (s, 1H), 9.32 (s, 1H); Mass Spectrum: M+H⁺ 471 and 473.

[0859] [58] The reactants were5-[N-(tert-butoxycarbonyl)piperidin-4-yloxy]-4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxyquinazolineand 2-fluoroethanol. The reaction mixture was stirred at ambienttemperature for 1 hour. Thereafter, a 6M solution of hydrogen chloridein diethyl ether was added and the reaction mixture was stirred atambient temperature for 1 hour. The resultant precipitate was isolated,washed with ethyl acetate and diethyl ether and dried. There was thusobtained the required product,4-(6-chloro-2,3-methylenedioxyanilino)-7-(2-fluoroethoxy)-5-piperidin-4-yloxyquinazoline;NMR Spectrum: (CDCl₃) 1.8-2.0 (m, 2H), 2.2-2.3 (m, 2H), 2.8-2.9 (m, 2H),3.1-3.3 (m, 2H), 4.3 (m, 1H), 4.4 (m, 1H), 4.7 (m, 1H), 4.8 (m, 1H), 4.9(m, 1H), 6.08 (s, 2H), 6.6 (d, 1H), 6.75 (d, 1H), 6.82 (d, 1H), 7.0 (d,1H), 8.55 (s, 1H), 9.35 (s, 1H); Mass Spectrum: M+H⁺ 461 and 463.

[0860] [59] (2R,5R)-1-(2-Hydroxyethyl)-2,5-dimethoxymethylpyrrolidinewas used as a starting material and the reaction mixture was stirred atambient temperature for 2 hours. The reaction product was treated with6M hydrogen chloride in diethyl ether to give the dihydrochloride salt.A portion thereof was treated with a saturated methanolic ammoniasolution, the mixture was filtered and the filtrate evaporated to givethe free base which gave the following data: NMR Spectrum: (CDCl₃)1.6-1.7 (m, 4H), 1.9-2.1 (m, 2H), 2.22 (m, 2H), 3.15-3.5 (m, 8H), 3.33(s, 6H), 3.6 (m, 2H), 4.08 (m, 2H), 4.12 (m, 2H), 4.75 (m, 1H), 6.05 (s,2H), 6.58 (d, 1H), 6.7 (d, 1H), 6.9 (d, 1H), 6.95 (m, 1H), 8.1 (d, 1H),8.6 (s, 1H), 9.75 (s, 1H); Mass Spectrum: M+H⁺ 567.

[0861] [60] The reaction mixture was stirred at ambient temperature for3 hours. The reaction product was purified by column chromatography onsilica using a 24:1 mixture of methylene chloride and a saturatedmethanolic ammonia solution as eluent. The resultant product gave thefollowing data: Mass Spectrum: M+H⁺ 503.

[0862] [61] The reaction mixture was stirred at ambient temperature for3 hours. The reaction product was purified by column chromatography onsilica using increasingly polar mixtures of methylene chloride and asaturated methanolic ammonia solution as eluent. The resultant productgave the following data: Mass Spectrum: M+H⁺ 473.

[0863] [62] The reaction mixture was stirred at ambient temperature for3 hours. The reaction product was purified by column chromatography onsilica using increasingly polar mixtures of methylene chloride and asaturated methanolic ammonia solution as eluent. The resultant productgave the following data: Mass Spectrum: M+H⁺ 473.

[0864] [63] (2S)-1-(2-Hydroxyethyl)-N-methylprolinamide was used as astarting material and the reaction mixture was stirred at ambienttemperature for 3 hours. The reaction product gave the following data:Mass Spectrum: M+H⁺ 536.

[0865] [64] (2S)-1-(2-Hydroxyethyl)-2-morpholinocarbonylpyrrolidine wasused as a starting material and the reaction mixture was stirred atambient temperature for 3 hours. The reaction product gave the followingdata: Mass Spectrum: M+H⁺ 592.

[0866] [65](2S)-1-(2-Hydroxyethyl)-2-(4-methylpiperazin-1-ylcarbonyl)pyrrolidinewas used as a starting material and the reaction mixture was stirred atambient temperature for 3 hours. The reaction product gave the followingdata: Mass Spectrum: M+H⁺ 605.

[0867] [66](2S)-1-(2-Hydroxyethyl)-2-(pyrrolidin-1-ylcarbonyl)pyrrolidine was usedas a starting material and the reaction mixture was stirred at ambienttemperature for 3 hours. The reaction product gave the following data:Mass Spectrum: M+H⁺ 576.

[0868] [67] (2S)-1-(2-Hydroxyethyl)-2-piperidinocarbonylpyrrolidine wasused as a starting material and the reaction mixture was stirred atambient temperature for 3 hours. The reaction product gave the followingdata: Mass Spectrum: M+H⁺ 590.

[0869] [68] (2S)-1-(2-Hydroxyethyl)prolinamide was used as a startingmaterial and the reaction mixture was stirred at ambient temperature for3 hours. The reaction product gave the following data: Mass Spectrum:M+H⁺ 522.

[0870] [69] (2R)-1-(2-Hydroxyethyl)-2-methylpyrrolidine was used as astarting material and the reaction mixture was stirred at ambienttemperature for 3 hours. The reaction product gave the following data:Mass Spectrum: M+H⁺ 493.

[0871] [70] (2S)-1-(2-Hydroxyethyl)-2-methoxymethylpyrrolidine was usedas a starting material and the reaction mixture was stirred at ambienttemperature for 3 hours. The reaction product gave the following data:Mass Spectrum: M+H⁺ 523.

[0872] [71] The reactants were4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-tetrahydropyran-4-yloxyquinazolineand 1-(tert-butoxycarbonyl)-4-(3-hydroxypropyl)piperazine and thereaction mixture was stirred at ambient temperature for 2 hours.Thereafter, trifluoroacetic acid (1 ml) was added and the mixture wasstirred at ambient temperature for 16 hours. The mixture was evaporatedand the residue was triturated under a saturated methanolic ammoniasolution (1 ml). Methylene chloride was added and the mixture wasfiltered. The filtrate was evaporated and the residue was purified bycolumn chromatography on silica using a 97:3 mixture of methylenechloride and a saturated methanolic ammonia solution as eluent. Thematerial so obtained was treated with a 6M solution of hydrogen chloridein diethyl ether. The precipitate was isolated, washed with diethylether and dried under vacuum to give the dihydrochloride salt (0.11 g)of the required product, a portion of which was converted to the freebase using an analogous procedure to that described in Example 3. Thefree base gave the following data: NMR Spectrum: (CDCl₃) 1.9-2.1 (m,4H), 2.2-2.3 (m, 2H), 2.3-2.5 (m, 4H), 2.55 (m, 2H), 2.91 (m, 4H), 3.65(m, 2H), 4.05 (m, 2H), 4.15 (m, 2H), 4.8 (m, 1H), 6.06 (s, 2H), 6.5 (d,1H), 6.72 (d, 1H), 6.84 (d, 1H), 6.97 (d, 1H), 8.5 (s, 1H), 9.26 (s,1H); Mass Spectrum: M+H⁺ 542 and 544.

[0873] The4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-tetrahydropyran-4-yloxyquinazolineused as a starting material was prepared as follows:

[0874] A mixture of7-benzyloxy-4-(6-chloro-2,3-methylenedioxyanilino)-5-tetrahydropyran-4-yloxyquinazoline(Example 17[34], 0.2 g) and trifluoroacetic acid (2 ml) was stirred andheated to 80° C. for 6 hours. The mixture was evaporated and the residuewas triturated under a 6M solution of hydrogen chloride in diethylether. The resultant solid was isolated, washed with diethyl ether anddried under vacuum. The solid was treated with a saturated methanolicammonia solution. The mixture was filtered, the filtrate was evaporatedand the residue was triturated under methylene chloride. The solid soobtained was washed with methylene chloride and dried under vacuum.There was thus obtained4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline(0.17 g); NMR Spectrum: (DMSOd₆) 1.8-1.9 (m, 2H), 2.05-2.2 (m, 2H),3.5-3.6 (m, 2H), 3.8-3.9 (m, 2H), 4.95 (m, 1H), 6.08 (s, 2H), 6.7 (d,1H), 6.8 (d, 1H), 6.95 (d, 1H), 7.05 (d, 1H), 8.35 (s, 2H), 9.32 (s,1H), 10.8 (br s, 1H); Mass Spectrum: M−H⁻ 414 and 416.

[0875] The 1-(tert-butoxycarbonyl)-4-(3-hydroxypropyl)piperazine used asa starting material was prepared using an analogous procedure to thatdescribed in European Patent Application No. 0388309:

[0876] A mixture of 3-bromopropanol (25 ml),1-(tert-butoxycarbonyl)piperazine (29 ml), potassium carbonate (83 g)and ethanol (200 mi) was stirred and heated to reflux for 20 hours. Themixture was cooled to ambient temperature and filtered. The filtrate wasevaporated and the residue was triturated under diethyl ether. Theresultant mixture was filtered and the filtrate was evaporated. Theresidue was purified by distillation to give the required startingmaterial as an oil.

[0877] [72] The reaction mixture was stirred at ambient temperature for2 hours. The reaction product was treated with 6M hydrogen chloride indiethyl ether to give the dihydrochloride salt of the product, a portionof which was converted to the free base using an analogous procedure tothat described in Example 3. The free base gave the following data: NMRSpectrum: (CDCl₃) 1.9-2.1 (m, 4H), 2.15-2.3 (m, 2H), 2.28 (s, 3H),2.4-2.7 (m, 10H), 3.6-3.7 (m, 2H), 4.0-4.1 (m, 2H), 4.15 (m, 2H), 4.75(m, 1H), 6.05 (s, 2H), 6.5 (d, 1H), 6.72 (d, 1H), 6.83 (d, 1H), 6.97 (d,1H), 8.52 (s, 1H), 9.26 (s, 1H); Mass Spectrum: M+H⁺ 556 and 558.

[0878] [73] The reaction mixture was stirred at ambient temperature for2 hours. The reaction product was treated with 6M hydrogen chloride indiethyl ether to give the dihydrochloride salt of the product, a portionof which was converted to the free base using an analogous procedure tothat described in Example 3. The free base gave the following data: NMRSpectrum: (CDCl₃) 1.9-2.05 (m, 2H), 2.2-2.3 (m, 2H), 2. 31 (s, 3H),2.4-2.7 (m, 8H), 2.87 (m, 2H), 2.55-2.7 (m, 2H), 3.95-4.05 (m, 2H), 4.25(m, 2H), 4.75 (m, 1H), 6.05 (s, 2H), 6.55 (d, 1H), 6.72 (d, 1H), 6.83(d, 1H), 6.97 (d, 1H), 8.52 (s, 1H), 9.26 (s, 1H); Mass Spectrum: M+H⁺542 and 544.

[0879] [74] The reaction mixture was stirred at ambient temperature for2 hours. The reaction product was treated with 6M hydrogen chloride indiethyl ether to give the dihydrochloride salt of the product, a portionof which was converted to the free base using an analogous procedure tothat described in Example 3. The free base gave the following data: NMRSpectrum: (CDCl₃) 1.4-1.5 (m, 2H), 1.6-1.7 (m, 4H), 1.9-2.05 (m, 2H),2.2-2.3 (m, 2H), 2.5 (br s, 4H), 2.82 (m, 2H), 3.62 (m, 2H), 4.05 (m,2H), 4.22 (m, 2H), 4.75 (m, 1H), 6.05 (s, 2H), 6.55 (d, 1H), 6.71 (d,1H), 6.83 (d, 1H), 6.97 (d, 1H), 8.52 (s, 1H), 9.27 (s, 1H); MassSpectrum: M+H⁺ 527 and 529.

[0880] [75] The reactants were4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-tetrahydropyran-4-yloxyquinazolineand N-(tert-butoxycarbonyl)-4-(2-hydroxyethyl)piperidine (J. Med. Chem.,1994, 37, 2721) and the reaction mixture was stirred at ambienttemperature for 2 hours. Thereafter, trifluoroacetic acid (1 ml) wasadded and the mixture was stirred at ambient temperature for 16 hours.The mixture was evaporated and the residue was triturated under asaturated methanolic ammonia solution (1 ml). Methylene chloride wasadded and the mixture was filtered. The filtrate was evaporated and theresidue was purified by column chromatography on silica using a 97:3mixture of methylene chloride and a saturated methanolic ammoniasolution as eluent. The material so obtained was treated with a 6Msolution of hydrogen chloride in diethyl ether. The precipitate wasisolated, washed with diethyl ether and dried under vacuum to give therequired product; NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 1.35-1.5 (m, 2H),1.75-1.95 (m, 5H), 2.0-2.15 (m, 4H), 2.8-2.95 (m, 2H), 3.3 (d, 2H), 3.55(m, 2H), 3.92 (m, 2H), 4.25 (m, 2H), 5.15 (m, 1H), 6.14 (s, 2H), 6.94(d, 1H), 7.04 (d, 1H), 7.13 (d, 1H), 7.15 (s, 1H), 8.84 (s, 1H); MassSpectrum: M+H⁺ 527 and 529.

[0881] [76] The reaction mixture was stirred at ambient temperature for2 hours. The reaction product was treated with 6M hydrogen chloride indiethyl ether to give the dihydrochloride salt of the product, a portionof which was converted to the free base using an analogous procedure tothat described in Example 3. The free base gave the following data: NMRSpectrum: (CDCl₃) 1.9-2.1 (m, 2H), 2.2-2.3 (m, 2H), 3.6-3.7 (m, 2H),4.0-4.1 (m, 2H), 4.42 (m, 2H), 4.5 (m, 2H), 4.8 (m, 1H), 6.06 (s, 2H),6.56 (d, 1H), 6.73 (d, 1H), 6.9 (m, 3H), 7.0 (d, 1H), 8.47 (d, 2H), 8.54(s, 1H), 9.28 (s, 1H); Mass Spectrum: M+H⁺ 537 and 539.

[0882] [77] The reaction mixture was stirred at ambient temperature for2 hours. The product gave the following data: NMR Spectrum: (CDCl₃)1.25-1.4 (m, 2H), 1.5 (s, 9H), 1.75-1.9 (m, 2H), 1.9-2.1 (m, 3H),2.2-2.3 (m, 2H), 2.7-2.8 (m, 2H), 3.6-3.7 (m, 2H), 3.95 (d, 2H), 4.0-4.1(m, 2H), 4.1-4.3 (m, 2H), 4.78 (m, 1H), 6.08 (s, 2H), 6.5 (d, 1H), 6.75(d, 1H), 6.82 (d, 1H), 6.97 (d, 1H), 8.52 (s, 1H), 9.28 (s, 1H); MassSpectrum: M+H⁺ 613 and 615.

[0883] [78] The reaction mixture was stirred at ambient temperature for1 hour. The reaction product gave the following data: NMR Spectrum:(CDCl₃) 1.6-1.75 (m, 4H), 1.75-1.9 (m, 6H), 2.0-2.2 (m, 4H), 2.55 (m,4H), 2.65 (m, 2H), 4.15 (m, 2H), 5.0 (m, 1H), 6.02 (s, 2H), 6.5 (d, 1H),6.65 (d, 1H), 6.8 (d, 1H), 6.9 (m, 1H), 8.12 (d, 1H), 8.58 (s, 1H), 8.8(s, 1H); Mass Spectrum: M+H⁺ 477.

[0884] [79] The reaction mixture was stirred at ambient temperature for1 hour. The reaction product gave the following data: NMR Spectrum:(CDCl₃) 1.65-1.8 (m, 4H), 1.9 (m, 2H), 2.0-2.2 (m, 8H), 2.3 (s, 3H),2.3-2.7 (m, 6H), 4.15 (t, 2H), 5.0 (m, 1H), 6.02 (s, 2H), 6.5 (s, 1H),6.65 (d, 1H), 6.8 (d, 1H), 6.92 (m, 1H), 8.15 (d, 1H), 8.6 (s, 1H), 9.8(s, 1H); Mass Spectrum: M+H⁺ 506.

[0885] [80] The reaction mixture was stirred at ambient temperature for1 hour. The reaction product gave the following data: NMR Spectrum:(CDCl₃) 1.65-1.8 (m, 2H), 1.8-1.95 (m, 2H), 1.95-2.2 (m, 4H), 2.3 (s,3H), 2.4-2.6 (m, 4H), 2.6-2.8 (m, 4H), 2.9 (m, 2H), 4.2 (m, 2H), 5.0 (m,1H), 6.0 (s, 2H), 6.52 (d, 1H), 6.65 (d, 1H), 6.8 (d, 1H), 6.9 (m, 1H),8.15 (d, 1H), 8.6 (s, 1H), 9.8 (s, 1H); Mass Spectrum: M+H⁺ 492.

[0886] [81] The reaction mixture was stirred at ambient temperature for1 hour. The reaction product gave the following data: NMR Spectrum:(CDCl₃) 1.6-1.7 (m, 6H), 1.7-1.8 (m, 2H), 1.8-1.95 (m, 2H), 2.0-2.2 (m,4H), 2.55 (br s, 4H), 2.82 (m, 2H), 4.22 (m, 2H), 5.0 (m, 1H), 6.02 (s,2H), 6.52 (s, 1H), 6.65 (d, 1H), 6.8 (d, 1H), 6.9 (m, 1H), 8.15 (d, 1H),8.6 (s, 1H), 9.8 (s, 1H); Mass Spectrum: M+H⁺ 477.

[0887] [82](2S)-1-(2-Hydroxyethyl)-2-(4-methylpiperazin-1-ylcarbonyl)pyrrolidinewas used as a starting material and the reaction mixture was stirred atambient temperature for 1 hour. The reaction product gave the followingdata: Mass Spectrum: M+H⁺ 589.

[0888] [83] N-(tert-Butoxycarbonyl)piperidin-4-ylmethanol was used as areactant. The reaction mixture was stirred at ambient temperature for 1hour. Thereafter, a 6M solution of hydrogen chloride in diethyl ether (2ml) was added and the reaction mixture was stirred at ambienttemperature for 16 hours. The mixture was diluted with methylenechloride (10 ml) and a saturated methanolic ammonia solution (3 ml) wasadded. The mixture was filtered and the filtrate was evaporated todryness. The residue was purified by column chromatography on silicausing a 50:47:3 mixture of methylene chloride, ethyl acetate and asaturated methanolic ammonia solution as eluent. The reaction productgave the following data: NMR Spectrum: (CDCl₃) 1.25-1.42 (m, 2H),1.6-1.7 (m, 4H), 1.8-2.0 (m, 3H), 2.0-2.2 (m, 4H), 2.7 (m, 2H), 3.15 (d,2H), 3.95 (d, 2H), 5.05 (m, 1H), 6.02 (s, 2H), 6.5 (d, 1H), 6.65 (d,1H), 6.8 (d, 1H), 6.9 (m, 1H), 8.15 (d, 1H), 8.6 (s, 1H), 8.8 (s, 1H);Mass Spectrum: M+H⁺ 463.

[0889] [84] 1-(tert-Butoxycarbonyl)-4-(3-hydroxypropyl)piperazine wasused as a reactant. The reaction mixture was stirred at ambienttemperature for 1 hour. Thereafter, a 6M solution of hydrogen chloridein diethyl ether (2 ml) was added and the reaction mixture was stirredat ambient temperature for 16 hours. The mixture was diluted withmethylene chloride (10 ml) and a saturated methanolic ammonia solution(3 ml) was added. The mixture was filtered and the filtrate wasevaporated to dryness. The residue was purified by column chromatographyon silica using a 50:47:3 mixture of methylene chloride, ethyl acetateand a saturated methanolic ammonia solution as eluent. The reactionproduct gave the following data: NMR Spectrum: (CDCl₃) 1.9-2.1 (m, 2H),1.8-1.95 (m, 2H), 1.95-2.2 (m, 6H), 1.9 (br s, 4H), 1.95 (m, 2H), 2.9(m, 4H), 4.15 (m, 2H), 5.0 (m, 1H), 6.02 (s, 2H), 6.5 (d, 1H), 6.65 (d,1H), 6.8 (d, 1H), 6.9 (m, 1H), 8.12 (d, 1H), 8.6 (s, 1H), 8.8 (s, 1H);Mass Spectrum: M+H⁺ 492.

EXAMPLE 15

[0890] Using an analogous procedure to that described in Example 5, theappropriate 4-chloroquinazoline was reacted with the appropriate anilinein the presence of hydrogen chloride to give the dihydrochloride saltsof the compounds described in Table IV, a portion of each of which wasconverted to the free base. TABLE IV

No. and Note (R¹)_(m) Q¹ (R²)_(n) [1] 7-methoxy piperidin-4-ylmethyl2-bromo-5-methoxy [2] 7-methoxy piperidin-4-ylmethyl 2-chloro-5-methoxy[3] 7-methoxy piperidin-4-ylmethyl 2,5-dimethoxy [4] 7-methoxypiperidin-4-ylmethyl 2,5-dichloro [5] 7-methoxy piperidin-4-ylmethyl2,3-methylenedioxy [6] 7-methoxy N-methylpiperidin-4-yl 2,5-dichloro [7]7-methoxy N-methylpiperidin-4-yl 2-bromo-5-chloro [8] 7-benzyloxypiperidin-4-yl 2-bromo-5-methoxy ]9] 6-methoxy N-methylpiperidin-4-yl2-chloro-5-methoxy [10] 7-[3-(4-methylpiperazin-1- 4-tetrahydropyranyl2,4-dichloro-5-methoxy yl)propoxy] [11] 6-[3-(4-methylpiperazin-1-4-tetrahydropyranyl 2-chloro-5-methoxy yl)propoxy] [12]6-[3-(4-methylpiperazin-1- 4-tetrahydropyranyl 2,5-dichloro yl)propoxy][13] 6-[3-(4-methylpiperazin-1- 4-tetrahydropyranyl 2-bromo-5-methoxyyl)propoxy] [14] 7-[3-(4-methylpiperazin-1- 4-tetrahydropyranyl4-chloro-2-fluoro- yl)propoxy] 5-methoxy [15] 7-[3-(4-methylpiperazin-1-4-tetrahydropyranyl 4-bromo-2-fluoro yl)propoxy] [16]7-[3-(4-methylpiperazin-1- 4-tetrahydropyranyl 2-pyrrolidin-1-yl-yl)propoxy] 5-methoxy [17] 7-[3-(4-methylpiperazin-1-4-tetrahydropyranyl 2,3-methylenedioxy yl)propoxy] [18] 7-benzyloxyN-tert-butoxycarbonyl- 6-chloro- piperidin-4-yl 2,3-methylenedioxy [19]7-hydroxy cyclopentyl 2,3-methylenedioxy

[0891] Notes

[0892] [1] The reactants were5-[N-(tert-butoxycarbonyl)piperidin-4-ylmethoxy]-4-chloro-7-methoxyquinazolineand 2-bromo-5-methoxyaniline hydrochloride and the reaction mixture washeated to 80° C. for 2 hours. A second portion of 6M hydrogen chloridein isopropanol (0.06 ml) was added and the reaction mixture was heatedto 80° C. for a further 4 hours. The reaction product was obtained asthe dihydrochloride salt, a portion of which was converted to the freebase which gave the following data: NMR Spectrum: (CDCl₃) 1.3 (m, 2H),1.9 (d, 2H), 2.3 (m, 1H), 2.68 (m, 2H), 3.12 (d, 2H), 3.85 (s, 3H), 3.95(s, 3H), 4.15 (d, 2H), 6.52 (d, 1H), 6.62 (m, 1H), 6.88 (s, 1H), 7.5 (d,1H), 8.22 (d, 1H), 8.6 (s, 1H), 8.9 (s, 1H); Mass Spectrum: M+H⁺ 473 and475.

[0893] The5-[N-(tert-butoxycarbonyl)piperidin-4-ylmethoxy]4-chloro-7-methoxyquinazolineused as a starting material was prepared as follows:

[0894] Diethyl azodicarboxylate (3.85 ml) was added dropwise to astirred mixture of5-hydroxy-7-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (5g), N-(tert-butoxycarbonyl)piperidin-4-ylmethanol (4.2 g),triphenylphosphine (6.4 g) and methylene chloride (50 ml) which had beencooled to 10° C. The mixture was stirred at ambient temperature for 1hour. The resultant mixture was poured onto a column of silica andeluted with increasingly polar mixtures of methylene chloride and ethylacetate. The product so obtained was dissolved in a saturated methanolicammonia solution (250.ml) and solid sodium hydroxide (0.65 g) was added.The resultant mixture was stirred at ambient temperature for 30 minutes.The mixture was evaporated and the residue was purified by columnchromatography on silica using increasingly polar mixtures of methylenechloride and ethyl acetate and then methylene chloride, ethyl acetateand methanol as eluent. The product so obtained was triturated underdiethyl ether. The resultant solid was isolated, washed with diethylether and dried under vacuum. There was thus obtained5-[N-(tert-butoxycarbonyl)piperidin-4-ylmethoxy]-7-methoxy-3,4-dihydroquinazolin-4-one(3.4 g); NMR Spectrum: (CDCl₃) 1.3-1.4 (m, 2H), 1.46 (s, 9H), 1.95 (d,2H), 2.15 (m, 1H), 2.35 (t, 2H), 3.9 (s, 3H), 3.9 (m, 2H), 4.15 (br s,2H), 6.45 (d, 1H), 6.75 (d, 1H), 7.93 (s, 1H), 11.0 (br s, 10H); MassSpectrum: M+H⁺ 390.

[0895] A mixture of a portion (2.9 g) of the material so obtained,triphenyl phosphine (5.3 g), carbon tetrachloride (3 ml) and1,2-dichloroethane (50 ml) was stirred and heated to 70° C. for 2.5hours. The mixture was poured onto silica and eluted with increasinglypolar mixtures of methylene chloride and ethyl acetate. The material soobtained was triturated under diethyl ether. The resultant precipitatewas isolated, washed with diethyl ether and dried. There was thusobtained5-[N-(tert-butoxycarbonyl)piperidin-4-ylmethoxyl-4-chloro-7-methoxyquinazoline(1.9 g); NMR Spectrum: (CDCl₃) 1.35-1.5 (m, 2H), 1.45 (s, 9H), 1.92 (d,2H), 2.15 (m, 1H), 2.8 (t, 2H), 3.95 (d, 2H), 3.97 (s, 3H), 4.2 (br s,2H), 6.6 (d, 1H), 6.98 (d, 1H), 8.82 (s, 1H).

[0896] [2] The reactants were5-N-(tert-butoxycarbonyl)piperidin-4-ylmethoxy]-4-chloro-7-methoxyquinazolineand 2-chloro-5-methoxyaniline and the reaction mixture was heated to 80°C. for 2 hours. A second portion of 6M hydrogen chloride in isopropanol(0.06 ml) was added and the reaction mixture was heated to 80° C. for afurther 4 hours. The reaction product was obtained as thedihydrochloride salt, a portion of which was converted to the free basewhich gave the following data: NMR Spectrum: (CDCl₃) 1.3-1.4 (m, 2H),1.92 (d, 2H), 2.3 (m, 1H), 2.7 (t, 2H), 3.2 (d, 2H), 3.85 (s, 3H), 3.95(s, 3H), 4.15 (d, 2H), 6.52 (s, 1H), 6.65 (m, 1H), 6.9 (s, 1H), 7.32 (d,1H), 8.4 (s, 1H), 8.62 (s, 1H), 10.2 (s, 1H); Mass Spectrum: M+H⁺ 429and 431.

[0897] [3] The reactants were5-[N-(tert-butoxycarbonyl)piperidin-4-ylmethoxy]4-chloro-7-methoxyquinazolineand 2,5-dimethoxyaniline and the reaction mixture was heated to 80° C.for 2 hours. The reaction mixture was evaporated and the residue wasdissolved in methylene chloride (1 ml). Trifluoroacetic acid (1 ml) wasadded and the mixture was stirred at ambient temperature for 15 minutes.The resultant mixture was evaporated and the residue was partitionedbetween ethyl acetate and 1N aqueous sodium hydroxide solution. Theorganic layer was washed with brine, dried over magnesium sulphate andevaporated. The residue was dissolved in isopropanol (1 ml) and 6Mhydrogen chloride in isopropanol (0.1 ml) was added. The resultantprecipitate was isolated, washed with isopropanol and with diethyl etherand dried under vacuum. There was thus obtained the required product asthe dihydrochloride salt, a portion of which was converted to the freebase which gave the following data: NMR Spectrum: (CDCl₃) 1.3-1.5 (m,2H), 1.95 (d, 2H), 2.25 (m, 1H), 2.7 (m, 2H), 3.2 (d, 2H), 3.84 (s, 3H),3.92 (s, 3H), 3.93 (s, 3H), 4.1 (d, 2H), 6.5 (s, 1H), 6.6 (m, 1H), 6.9(m, 2H), 8.52 (d, 1H), 8.6 (s, 1H), 10.15 (s, 1H); Mass Spectrum: M+H⁺425.

[0898] [4] The reactants were5-[N-(tert-butoxycarbonyl)piperidin-4-ylmethoxy]4-chloro-7-methoxyquinazolineand 2,5-dichloroaniline and the reaction mixture was heated to 80° C.for 2 hours. The reaction mixture was evaporated and the residue wasdissolved in methylene chloride (1 ml). Trifluoroacetic acid (1 ml) wasadded and the mixture was stirred at ambient temperature for 15 minutes.The resultant mixture was evaporated and the residue was partitionedbetween ethyl acetate and 1N aqueous sodium hydroxide solution. Theorganic layer was washed with brine, dried over magnesium sulphate andevaporated. The residue was purified by column chromatography on silicausing a 9:10:1 mixture of methylene chloride, ethyl acetate and methanolas eluent. The material so obtained was dissolved in isopropanol (1 ml)and 6M hydrogen chloride in isopropanol (0.1 ml) was added. Theresultant precipitate was isolated, washed with isopropanol and withdiethyl ether and dried under vacuum. There was thus obtained therequired product as the dihydrochloride salt, a portion of which wasconverted to the free base which gave the following data: NMR Spectrum:(CDCl₃) 1.25-1.4 (m, 2H), 1.9 (d, 2H), 2.25 (m, 1H), 2.65 (m, 2H), 3.15(d, 2H), 3.95 (s, 3H), 4.12 (d, 2H), 6.55 (d, 1H), 6.9 (d, 1H), 7.05 (m,1H), 7.35 (d, 1H), 8.6 (s, 1H), 8.87 (d, 1H), 10.09 (br s, 1H); MassSpectrum: M+H⁺ 433 and 435.

[0899] [5] The reactants were5-[N-(tert-butoxycarbonyl)piperidin-4-ylmethoxy]-4-chloro-7-methoxyquinazolineand 2,3-methylenedioxyaniline and the reaction mixture was heated to 80°C. for 2 hours. The reaction mixture was evaporated and the residue wasdissolved in methylene chloride (1 ml). Trifluoroacetic acid (1 ml) wasadded and the mixture was stirred at ambient temperature for 15 minutes.The resultant mixture was evaporated and the residue was partitionedbetween ethyl acetate and 1N aqueous sodium hydroxide solution. Theorganic layer was washed with brine, dried over magnesium sulphate andevaporated. The residue was dissolved in isopropanol (1 ml) and 6Mhydrogen chloride in isopropanol (0.1 ml) was added. The resultantprecipitate was isolated, washed with isopropanol and with diethyl etherand dried under vacuum. There was thus obtained the required product asthe dihydrochloride salt, a portion of which was converted to the freebase which gave the following data: NMR Spectrum: (CDCl₃) 1.25-1.4 (m,2H), 1.85 (d, 2H), 2.2 (m, 1H), 2.65 (m, 2H), 3.2 (d, 2H), 3.9 (s, 3H),4.02 (d, 2H), 6.0 (s, 2H), 6.48 (d, 1H), 6.62 (d, 1H), 6.85 (d, 1H), 6.9(m, 1H), 8.07 (d, 1H), 8.58 (s, 1H), 9.6 (s, 1H); Mass Spectrum: M+H⁺409.

[0900] [6] The free base gave the following data: NMR Spectrum: (CDCl₃)1.95-2.1 (m, 2H), 2.15-2.35 (m, 4H), 2.3 (s, 3H), 2.85 (m, 2H), 3.92 (s,3H), 4.5 (m, 1H), 6.55 (d, 1H), 6.85 (d, 1H), 7.03 (m, 1H), 7.3 (d, 1H),8.6 (s, 1H), 8.85 (s, 1H); Mass Spectrum: M+H⁺ 433 and 435.

[0901] [7] The free base gave the following data: NMR Spectrum: (CDCl₃)2.0-2.15 (m, 2H), 2.15-2.3 (m, 4H), 2.28 (s, 3H), 2.85 (m, 2H), 3.92 (s,3H), 4.5 (m, 1H), 6.5 (s, 1H), 6.85 (s, 1H), 7.0 (m, 1H), 7.5 (d, 1H),8.35 (s, 1H), 8.55 (s, 1H), 9.7 (s, 1H); Mass Spectrum: M+H⁺ 477, 479and 481.

[0902] [8] The reactants were7-benzyloxy-5-[N-(tert-butoxycarbonyl)piperidin-4-yloxy]-4-chloroquinazolineand 2-bromo-5-methoxyaniline hydrochloride and the reaction mixture washeated to 80° C. for 2 hours. A second portion of 6M hydrogen chloridein isopropanol (0.06 ml) was added and the reaction mixture was heatedto 80° C. for a further 4 hours. The reaction product was obtained asthe dihydrochloride salt, a portion of which was converted to the freebase which gave the following data: NMR Spectrum: (CDCl₃) 1.95-2.1 (m,2H), 2.25 (d, 2H), 2.8 (m, 2H), 3.22 (m, 2H), 3.78 (s, 3H), 4.6 (m, 1H),5.12 (s, 3H), 6.58 (m, 2H), 6.9 (d, 1H), 7.25-7.5 (m, 5H), 7.89 (d, 1H),8.5 (s, 1H), 9.6 (s, 1H); Mass Spectrum: M+H⁺ 535 and 537.

[0903] The7-benzyloxy-5-[N-(tert-butoxycarbonyl)piperidin-4-yloxy]-4-chloroquinazolineused as a starting material was prepared as follows:

[0904] A mixture of 5,7-dibenzyloxy-3,4-dihydroquinazolin-4-one (2 g),magnesium bromide (1 g) and pyridine (10 ml) was stirred and heated to120° C. for 20 minutes. The mixture was evaporated and the residue wasdissolved in a mixture of water (20 ml) and glacial acetic acid (4 ml)and stirred for 10 minutes. The resultant precipitate was isolated,washed with water and dried under vacuum over phosphorus pentoxide at50° C. There was thus obtained7-benzyloxy-5-hydroxy-3,4-dihydroquinazolin-4-one (1.5 g); NMR Spectrum:(DMSOd₆) 5.22 (s, 2H), 6.5 (d, 1H), 6.7 (d, 1H), 7.3-7.5 (m, 5H), 8.05(s, 1H); Mass Spectrum: M+H⁺ 269.5.

[0905] The material so obtained was added portionwise to a stirredsuspension of sodium hydride (60% dispersion in mineral oil, 0.46 g;washed with pentane) in DMF (15 ml) which was cooled to 0° C. Themixture was stirred at ambient temperature for 30 minutes. The resultantmixture was cooled at 0°C., chloromethyl pivalate (1.2 ml) was added andthe mixture was stirred at ambient temperature for 1 hour. The mixturewas poured into water (70 ml) containing acetic acid (4 ml) and theresultant precipitate was isolated and dried under vacuum. The materialso obtained was dissolved in methylene chloride and the organic solutionwas dried over magnesium sulphate and evaporated. The residue wastriturated under pentane and the resultant solid was isolated and driedunder vacuum. There was thus obtained7-benzyloxy-5-hydroxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one(1.95 g); NMR Spectrum: (CDCl₃) 1.2 (s, 9H), 5.12 (s, 2H), 5.88 (s, 2H),6.58 (d, 1H), 6.72 (d, 1H), 7.3-7.5 (m, 5H), 8.15 (s, 1H), 11.32 (s,1H); Mass Spectrum: M+H⁺ 383.

[0906] The material so obtained was reacted withN-(tert-butoxycarbonyl)-4-hydroxypiperidine using an analogous procedureto that described in the first paragraph of the portion of Note [1]immediately above that is concerned with the preparation of startingmaterials. There was thus obtained7-benzyloxy-5-[N-(tert-butoxycarbonyl)piperidin-4-yloxy]-3,4-dihydroquinazolin-4-one(1.4 g); NMR Spectrum: (CDCl₃) 1.5 (s, 9H), 1.82 (m, 4H), 3.52 (m, 2H),3.7 (m, 2H), 4.65 (m, 1H), 5.2 (s, 2H), 6.6 (d, 1H), 6.9 (d, 1H),7.3-7.5 (m, 5H), 7.92 (s, 1H), 10.56 (br s, 1H); Mass Spectrum: M+H⁺452.6.

[0907] A mixture of the material so obtained, triphenylphosphine (1.66g), carbon tetrachloride (0.92 ml) and 1,2-dichloroethane (40 ml) wasstirred and heated to 70° C. for 1.5 hours. The mixture was evaporatedand the residue was purified by column chromatography on silica using a9:1 mixture of methylene chloride and ethyl acetate as eluent. There wasthus obtained7-benzyloxy-5-[N-(tert-butoxycarbonyl)piperidin-4-yloxy]-4-chloroquinazoline(1.1 g); NMR Spectrum: (CDCl₃) 1.5 (s, 9H), 1.98 (m, 4H), 3.5-3.7 (m,4H), 4.75 (m, 1H), 5.2 (s, 2H), 6.7 (d, 1H), 7.08 (d, 1H), 7.32-7.52 (m,5H), 8.82 (s, 1H); Mass Spectrum: M+H⁺ 470.

[0908] [9] The free base gave the following data: NMR Spectrum: (CDCl₃)1.95-2.15 (m, 6H), 2.25 (s, 3H), 2.85 (br s, 2H), 3.87 (s, 3H), 4.02 (s,3H), 4.45 (m, 1H), 6.65 (m, 1H), 7.35 (d, 1H), 7.55 (d, 1H), 7.7 (d,1H), 8.5 (d, 1H), 8.6 (s, 1H), 10.45 (br s, 1H); Mass Spectrum: M+H⁺ 429and 431.

[0909] The 4-chloro-6-methoxy-5-(N-methylpiperidin-4-yloxy)quinazolineused as a starting material was prepared as follows:

[0910] A solution of ferrous sulphate heptahydrate (99 g) in water (410ml) that had been heated to 70° C. was added to a mixture of2-benzyloxy-3-methoxy-6-nitrobenzoic acid (Bull. Soc. Chim. France,1965, 1417; 15.5 g) and concentrated aqueous ammonium hydroxide (370 ml)which was heated to 70° C. The resultant mixture was heated to refluxfor minutes. The mixture was filtered and the basicity of the filtratewas adjusted to pH8 by the addition of 2N aqueous hydrochloric acid andthen the filtrate was acidified to pH4 by the addition of 1M aqueouscitric acid solution. The mixture was partitioned between ethyl acetateand water. The organic layer was washed with water and with brine, driedover magnesium sulphate and evaporated to give6-amino-2-benzyloxy-3-methoxybenzoic acid (12.15 g); NMR Spectrum:(CDCl₃) 3.9 (s, 3H), 5.22 (s, 2H), 6.5 (d, 1H), 7.05 (d, 1H), 7.35-7.55(m, 5H): Mass Spectrum: M+H⁺ 274.

[0911] A mixture of the material so obtained, triazine (3.6 g),piperidine (3 ml) and ethanol (275 ml) was stirred and heated to refluxfor 16 hours. The mixture was cooled to ambient temperature. Theprecipitate was isolated, washed with ethanol and with diethyl ether anddried under vacuum to give5-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (10.3 g); NMRSpectrum: (CDCl₃) 3.9 (s, 3H), 5.15 (s, 2H), 7.2-7.45 (m, 4H), 7.5 (d,1H), 7.62 (d, 2H), 7.8 (s, 1H), 11.1 (br s, 1H); Mass Spectrum: M+H⁺283.

[0912] A solution of a portion (5 g) of the material so obtained intrifluoroacetic acid (50 ml) was stirred at ambient temperature for 30minutes. The mixture was evaporated and the residue was dissolved inwater. The solution was basified to pH8.5 by the portionwise addition ofsodium bicarbonate. The resultant precipitate was isolated, washed withwater and dried under vacuum at 50° C. over phosphorus pentoxide. Therewas thus obtained 5-hydroxy-6-methoxy-3,4-dihydroquinazolin-4-one (3.4g); NMR Spectrum: (DMSOd₆) 3.85 (s, 3H), 7.12 (d, 1H), 7.52 (d, 1H),7.98 (s, 1H), 11.89 (s, 1H); Mass Spectrum: M+H⁺ 193.

[0913] The material so obtained was added to a stirred suspension ofsodium hydride (1.59 g of a 60% dispersion in mineral oil which waswashed with pentane) in DMF (18 ml) which was cooled to 0° C. Themixture was stirred at ambient temperature for 30 minutes. The mixturewas cooled to 0° C. and chloromethyl pivalate (4.1 ml) was addeddropwise. The mixture was stirred at ambient temperature for 1.5 hours.The resultant precipitate was isolated, washed with water and driedovernight under vacuum. The solid was dissolved in methylene chlorideand the solution was dried over magnesium sulphate. The solution wasevaporated and the residue was triturated under pentane. The resultantsolid was isolated and dried under vacuum. There was thus obtained5-hydroxy-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (4.6g); NMR Spectrum: (CDCl₃) 1.25 (s, 9H), 4.0 (s, 3H), 5.9 (s, 2H), 7.2(d, 1H), 7.38 (d, 1H), 8.08 (s, 1H), 11.5 (s, 1H); Mass Spectrum: M+H⁺307.

[0914] A solution of di-tert-butyl azodicarboxylate (1.75 g ) inmethylene chloride (3 ml) was added to a stirred mixture of5-hydroxy-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one(1.55 g), triphenylphosphine (1.99 g), 4-hydroxy-1-methylpiperidine(0.75 g) and methylene chloride (12 ml) which had been cooled to 5° C.The mixture was stirred at ambient temperature for 1 hour. The mixturewas evaporated and the residue was purified by column chromatography onsilica using a 9:10:1 mixture of methylene chloride, ethyl acetate and asaturated methanolic ammonia solution as eluent. The material soobtained was stirred in a saturated methanolic ammonia solution for 48hours. The mixture was evaporated and the residue was triturated underdiethyl ether. The resultant solid was washed with diethyl ether anddried under vacuum to give6-methoxy-5-(N-methylpiperidin-4-yloxy)-3,4-dihydroquinazolin-4-one(0.92 g); NMR Spectrum: (DMSOd₆) 1.7-1.9 (m, 4H), 1.95 (t, 2H), 2.15 (s,3H), 2.7 (m, 2H), 3.85 (s, 3H), 4.08 (m, 1H), 7.4 (d, 1H), 7.6 (d, 1H),7.85 (s, 1H), 11.8 (br s, 1H); Mass Spectrum: M+H⁺ 290.

[0915] A mixture of a portion (0.3 g) of the material so obtained,triphenylphosphine (0.54 g), carbon tetrachloride (0.3 ml) and1,2-dichloroethane (13 ml) was stirred and heated to 70° C. for 2.5hours. The mixture was evaporated and the residue was purified by columnchromatography on silica using a 10:9:1 mixture of ethyl acetate,methylene chloride and a saturated methanolic ammonia solution aseluent. There was thus obtained4-chloro-6-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline (0.22 g);NMR Spectrum: (CDCl₃) 1.82-2.1 (m, 6H), 2.25 (s, 3H), 2.85 (m, 2H), 4.0(s, 3H), 4.4 (m, 1H), 7.7 (d, 1H), 7.8 (d, 1H), 8.82 (s, 1H).

[0916] [10] The free base gave the following data: NMR Spectrum: (CDCl₃)2.02 (m, 4H), 2.2 (d, 2H), 2.4 (s, 3H), 2.5-2.8 (m, 10H), 3.55 (t, 2H),3.95 (s, 3H), 4.05 (m, 2H), 4.1 (t, 2H), 4.7 (m, 1H), 6.55 (d, 1H), 6.82(d, 1H), 7.4 (s, 1H), 8.35 (s, 1H), 8.55 (s, 1H), 9.82 (s, 1H); MassSpectrum: M+H⁺ 576 and 578.

[0917] The4-chloro-7-[3-(4-methylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazolineused as a starting material was prepared as follows:5-Hydroxy-7-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one(0.61 g) was reacted with 4-hydroxytetrahydropyran (0.23 ml) using ananalogous procedure to that described in the first paragraph of theportion of Note [1] immediately above that is concerned with thepreparation of starting materials. There was thus obtained7-methoxy-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (0.3 g);NMR Spectrum: (DMSOd₆) 1.6-1.75 (m, 2H), 1.9-2.0 (m, 2H), 3.52 (m, 2H),3.85 (s, 3H), 3.95 (m, 2H), 4.75 (m, 1H), 6.65 (d, 1l), 6.7 (m, 1H),7.92 (s, 1H).

[0918] A mixture of7-methoxy-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (4 g),thiophenol (2.2 ml), potassium carbonate (3 g) andN-methylpyrrolidin-2-one (40 ml) was stirred and heated to 200° C. for25 minutes. The mixture was evaporated and the residue was acidified bythe addition of 12N aqueous hydrochloric acid (2 ml). Methylene chloride(5 ml) was added. The resultant precipitate was isolated, washed in turnwith water and diethyl ether and dried under vacuum to give7-hydroxy-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (3.4 g);NMR Spectrum: (DMSOd₆) 1.6-1.75 (m, 2H), 1.9-2.0 (m, 2H), 3.45-3.6 (m,2H), 3.8 (m, 3H), 4.65 (m, 1H), 6.5 (d, 1H), 6.65 (m, 1H), 7.92 (s, 1H),10.4 (s, 1H), 11.5 (s, 1H); Mass Spectrum: M+H⁺ 263.

[0919] A mixture of7-hydroxy-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (3.2 g),pyridine (3.2 ml) and acetic anhydride (20 ml) was stirred and heated to100° C. for 2 hours. The mixture was evaporated. The residue wasdissolved in a mixture of methanol and water and stirred at ambienttemperature for 2 hours. The mixture was evaporated to remove themethanol and the residual aqueous layer was freeze-dried. The residuewas purified by column chromatography on silica using a 19:1 mixture ofmethylene chloride and methanol as eluent. There was thus obtained7-acetoxy-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (3.1 g);NMR Spectrum: (DMSOd₆) 1.7 (m, 2H), 1.92 (m, 2H), 2.3 (s, 3H), 3.5 (m,2H), 3.9 (m, 2H), 4.72 (m, 1H), 6.95 (d, 2H), 7.98 (s, 1H), 10.9 (br s,1H); Mass Spectrum: M+H⁺ 305.

[0920] A mixture of a portion (1.2 g) of the material so obtained,phosphoryl chloride (0.41 ml), di-isopropylethylamine (1.74 ml) and1,2-dichloroethane (30 ml) was stirred and heated to 80° C. for 2.5hours. The mixture was evaporated. The material so obtained wasdissolved in a saturated methanolic ammonia solution and stirred for 2.5hours. The mixture was evaporated and the residue was purified by columnchromatography on silica using a 97:3 mixture of methylene chloride andmethanol as eluent. There was thus obtained4-chloro-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline (0.5 g); NMRSpectrum: (DMSOd₆) 1.8 (m, 2H), 2.08 (m, 2H), 3.6 (m, 2H), 3.9 (m, 2H),4.9 (m, 1H), 6.9 (d, 2H), 8.76 (s, 1H); Mass Spectrum: M+H⁺ 281 and 283.

[0921] Di-tert-butyl azodicarboxylate (0.65 g) was added to a stirredmixture of 4-chloro-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline (0.5g), triphenylphosphine (0.75 g), 1-(3-hydroxypropyl)-4-methylpiperazine(0.34 g) and methylene chloride (20 ml) and the mixture was stirred atambient temperature for 1.5 hours. The mixture was poured onto a columnof silica and eluted initially with a 49:1 mixture of methylene chlorideand methanol followed by a 97:3 mixture of methylene chloride and asaturated methanolic ammonia solution. There was thus obtained4-chloro-7-[3-(4-methylpiperazin-4-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazoline(0.54 g); NMR Spectrum: (CDCl₃) 1.9-2.2 (m, 6H), 2.25 (s, 3H), 2.32-2.68(m, 10H), 3.68 (m, 2H), 4.05 (m, 2H), 4.15 (t, 2H), 4.72 (m, 1H), 6.58(d, 1H), 6.92 (d, 1H), 8.8 (s, 1H); Mass Spectrum: M+H⁺ 421 and 423.

[0922] [11] The free base gave the following data: NMR Spectrum: (CDCl₃)1.95-2.2 (m, 6H), 2.5 (s, 3H), 2.6-2.9 (m, 10H), 3.35 (m, 2H), 3.9 (s,3H), 4.02 (m, 2H), 4.25 (t, 2H), 4.6 (m, 1H), 6.65 (m, 1H), 7.35 (d,1H), 7.55 (d, 1H), 7.68 (d, 1H), 8.55 (s, 1H), 8.65 (s, 1H), 10.45 (s,1H); Mass Spectrum: M+H⁺ 542 and 544.

[0923] The4-chloro-6-[3-(4-methylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazolineused as a starting material was prepared as follows:

[0924] Di-tert-butyl azodicarboxylate (3.6 g ) was added portionwise toa stirred mixture of5-hydroxy-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (3g), triphenylphosphine (4.1 g), 4-hydroxytetrahydropyran (1.2 ml) andmethylene chloride (50 ml) and the mixture was stirred at ambienttemperature for 30 minutes. The mixture was evaporated and the residuewas stirred in a saturated methanolic ammonia solution for 7 hours. Themixture was evaporated and the residue was purified by columnchromatography on silica using a 9:10:1 mixture of methylene chloride,ethyl acetate and a saturated methanolic ammonia solution as eluent.There was thus obtained6-methoxy-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (2.3 g);NMR Spectrum: (DMSOd₆) 1.65-1.8 (m, 2H), 1.8-1.9 (m, 2H), 3.35 (m, 2H),3.9 (s, 3H), 3.92 (m, 2H), 4.3 (m, 1H), 7.42 (d, 1H), 7.6 (d, 1H), 7.9(s, 1H), 11.8 (br s, 1H); Mass Spectrum: M+H⁺ 277.

[0925] A mixture of a portion (1.9 g) of the material so obtained,thiophenol (1 ml), potassium carbonate (1.4 g) andN-methylpyrrolid-2-one (20 ml) was stirred and heated to 200° C. for 30minutes. The mixture was evaporated. The residue was dissolved in amixture of methylene chloride (25 ml), methanol (1 ml) and acetic acid(2 ml) and the solution was poured onto a column of silica and waseluted with a 9:10:1 mixture of methylene chloride, ethyl acetate andmethanol. The material so obtained was triturated under diethyl etherand the resultant solid was washed with diethyl ether and dried undervacuum. There was thus obtained6-hydroxy-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (1.65g); NMR Spectrum: (DMSOd₆) 1.7-1.9 (m, 4H), 3.2-3.4 (m, 2H), 3.92 (m,2H), 4.3 (m, 1H), 7.3 (d, 1H), 7.35 (d, 1H), 7.85 (s, 1H), 9.55 (br s,1H), 11.75 (br s, 1H); Mass Spectrum: M+H⁺ 263.

[0926] A mixture of a portion (0.7 g) of the material so obtained,piperidine (0.7 ml) and acetic anhydride (10 ml) was heated to refluxfor 1 hour. The mixture was evaporated. The residue was dissolved in a1:1 mixture of methanol and water (18 ml) and stirred at ambienttemperature for 1 hour. The resultant precipitate was isolated, washedwith water and dried under vacuum to give6-acetoxy-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (0.54g); NMR Spectrum: (CDCl₃) 1.8-2.0 (m, 2H), 2.0-2.1 (m, 2H), 2.4 (s, 3H),3.45 (m, 2H), 4.02 (m, 2H), 4.4 (m, 1H), 7.5-7.6 (m, 2H), 8.0 (s, 1H),10.5 (br s, 1H); Mass Spectrum: M+H⁺ 305.

[0927] A mixture of the material so obtained, triphenylphosphine (0.93g), carbon tetrachloride (0.515 ml) and 1,2-dichloroethane (24 ml) wasstirred and heated to 70° C. for 2.5 hours. The mixture was evaporatedand the residue was dissolved in a saturated methanolic ammonia solution(20 ml) and stirred at ambient temperature for 1 hour. The mixture wasfiltered and the filtrate was poured onto a column of silica and elutedin turn with methylene chloride, a 1:1 mixture of methylene chloride andethyl acetate and a 24:25:1 mixture of methylene chloride, ethyl acetateand methanol. There was thus obtained4-chloro-6-hydroxy-5-tetrahydropyran-4-yloxyquinazoline.

[0928] Using an analogous procedure to that described in the lastparagraph of the portion of Note [10] immediately above that isconcerned with the preparation of starting materials,4-chloro-6-hydroxy-5-tetrahydropyran-4-yloxyquinazoline (1.12 g) wasreacted with 1-(3-hydroxypropyl)-4-methylpiperazine to give4-chloro-6-[3-(4-methylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazoline(0.56 g); NMR Spectrum: (CDCl₃) 1.85-2.2 (m, 6H), 2.32 (s, 3H), 2.35-2.7(m, 10H), 3.42 (m, 2H), 4.05 (m, 2H), 4.25 (m, 2H), 4.65 (m, 1H), 7.75(d, 1H), 7.85 (d, 1H), 8.9 (s, 1H); Mass Spectrum: M+H⁺ 421 and 423.

[0929] [12] The free base gave the following data: NMR Spectrum: (CDCl₃)1.82-2.18 (m, 6H), 2.35 (s, 3H), 2.4-2.7 (m, 10H), 3.35 (m, 2H), 4.02(d, 2H), 4.25 (t, 2H), 4.65 (m, 1H), 7.08 (m, 1H), 7.4 (d, 1H), 7.6 (d,1H), 7.7 (d, 1H), 8.68 (s, 1H), 9.0 (s, 1H), 10.5 (s, 1H); MassSpectrum: M+H⁺ 546 and 548.

[0930] [13] The free base gave the following data: NMR Spectrum: (CDCl₃)1.9-2.15 (m, 6H), 2.35 (s, 3H), 2.4-2.75 (m, 10H), 3.35 (m, 2H), 3.89(s, 3H), 4.02 (m, 2H), 4.25 (t, 2H), 4.65 (m, 1H), 6.65 (m, 1H), 7.5 (d,1H), 7.55 (d, 1H), 7.65 (d, 1H), 8.35 (d, 1H), 8.6 (s, 1H), 10.28 (s,1H); Mass Spectrum: M+H⁺ 586 and 588.

[0931] [14] 4-Chloro-2-fluoro-5-methoxyaniline is disclosed inInternational Patent Application WO 86/02642. The free base of theproduct gave the following data: NMR Spectrum: (CDCl₃) 1.9-2.1 (m, 4H),2.22 (d, 2H), 2.27 (s, 3H), 2.32-2.62 (m, 10H), 3.55 (m, 2H), 3.94 (s,3H), 4.08 (m, 2H), 4.15 (t, 2H), 4.7 (m, 1H), 6.52 (s, 1H), 6.82 (s,1H), 7.15 (d, 1H), 8.6 (s, 1H), 8.8 (d, 1H), 10.1 (s, 1H); MassSpectrum: M+H⁺ 560 and 562.

[0932] [15] The free base gave the following data: NMR Spectrum: (CDCl₃)1.9-2.1 (m, 4H), 2.22 (d, 2H), 2.28 (s, 3H), 2.35-2.7 (m, 10H), 3.6 (m,2H), 4.08 (m, 2H), 4.12 (t, 2H), 4.7 (m, 1H), 6.5 (d, 1H), 6.82 (d, 1H),7.25-7.35 (m, 2H), 8.57 (s, 1H), 8.77 (m, 1H), 10.02 (s, 1H); MassSpectrum: M+H⁺ 574 and 576.

[0933] [16] 2-Pyrrolidin-1-yl-5-methoxyaniline is disclosed inInternational Patent Application WO 85/01939. The free base of theproduct gave the following data: NMR Spectrum: (CDCl₃) 1.8-2.0 (m, 8H),2.2 (d, 2H), 2.29 (s, 3H), 2.4-2.7 (m, 12H), 3.1 (t, 2H), 3.6 (m, 2H),3.82 (s, 3H), 4.02 (m, 2H), 4.15 (t, 2H), 4.7 (m, 1H), 6.5 (d, 1H), 6.65(m, 1H), 6.85 (d, 1H), 7.05 (d, 1H), 7.9 (d, 1H), 8.55 (s, 1H), 9.82 (s,1H); Mass Spectrum: M+H⁺ 577.

[0934] [17] The free base gave the following data: NMR Spectrum: (CDCl₃)1.95 (m, 4H), 2.18 (d, 2H), 2.25 (s, 3H), 2.3-2.6 (m, 10H), 3.55 (t,2H), 4.02 (m, 2H), 4.1 (t, 2H), 4.68 (m, 1H), 5.95 (s, 2H), 6.45 (s,1H), 6.6 (d, 1H), 6.78 (s, 1H), 6.85 (m, 1H), 8.02 (d, 1H), 8.5 (s, 1H),9.68 (s, 1H); Mass Spectrum: M+H⁺ 522.

[0935] [18] The reactants were7-benzyloxy-5-[N-(tert-butoxycarbonyl)piperidin-4-yloxy]-4-chloroquinazoline(1.92 g) and 6-chloro-2,3-methylenedioxyaniline (0.771 g) and thereaction mixture was heated to reflux for 1.5 hours. The reactionmixture was cooled to ambient temperature and the precipitate wasisolated, washed in turn with isopropanol, ethyl acetate and diethylether and dried under vacuum. The material so obtained was dissolved ina 2M solution of hydrogen chloride in diethyl ether and stirred atambient temperature for 2 hours. The resultant solid was isolated,washed with diethyl ether and dried under vacuum. There was thusobtained the required compound as a dihydrochloride salt (2.4 g) whichgave the following data: NMR Spectrum: (DMSOd₆) 1.4 (s, 9H), 1.8-1.95(m, 2H), 2.0-2.1 (m, 2H), 2.9-3.1 (m, 2H), 3.4 (m, 2H), 5.08 (m, 1H),5.35 (s, 2H), 6.12 (s, 2H), 7.0-7.05 (m, 2H), 7.12 (d, 1H), 7.22 (d,1H), 7.3-7.6 (m, 5H), 8.75 (s, 1H), 10.1 (s, 1H); Mass Spectrum: M+H⁺605 and 607.

[0936] [19] The reactants were7-acetoxy-4-chloro-5-cyclopentyloxyquinazoline and2,3-methylenedioxyaniline. The precipitate from the reaction mixture wasisolated, dissolved in a saturated methanolic ammonia solution (20 ml)and stirred at ambient temperature for 2 hours. The mixture wasevaporated and the residue was triturated under water. The solid soobtained was washed with water and dried overnight under vacuum. Theproduct gave the following data: NMR Spectrum: (DMSOd₆) 1.6-1.7 (m, 2H),1.7-1.9 (m, 2H), 1.9-2.15 (m, 4H), 5.1 (br s, 1H), 6.12 (s, 2H), 6.63(s, 1H), 6.65 (s, 1H), 6.72 (d, 1H), 6.9 (m, 1H), 8.15 (d, 1H), 8.42 (s,1H), 9.8 (s, 1H), 10.58 (s, 1H); Mass Spectrum: M+H⁺ 366.

EXAMPLE 164-(2-iodoanilino)-7-methoxy-5-N-methylpiperidin-4-yloxy)quinazolinedihydrochloride

[0937] A mixture of4-chloro-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline (0.08 g),2-iodoaniline (0.068 g), 6M hydrogen chloride in isopropanol (0.05 ml)and isopropanol (3 ml) was stirred and heated to 80° C. for 2 hours. Themixture was cooled to 0° C. and diethyl ether was added. The resultantprecipitate was isolated, washed with diethyl ether and dried undervacuum. The solid so obtained was dissolved in methylene chloride andthe solution was washed with a saturated aqueous sodium bicarbonatesolution. The organic solution was poured onto a column of silica andeluted with a 9:10:1 mixture of methylene chloride, ethyl acetate andmethanol followed by a 9:10:1 mixture of methylene chloride, ethylacetate and a saturated methanolic ammonia solution. The material soobtained was dissolved in diethyl ether and 6M hydrogen chloride indiethyl ether (0.1 ml) was added. The resultant precipitate wasisolated, washed with diethyl ether and dried under vacuum. There wasthus obtained the title compound (0.081 g), as the dihydrochloride salt,a portion of which was converted to the free base using an analogousprocedure to that described in Example 3. The free base gave thefollowing data: NMR Spectrum: (CDCl₃) 2.1-2.4 (m, 6H), 2.3 (s, 3H), 2.8(m, 2H), 3.92 (s, 3H), 4.6 (m, 1H), 6.55 (s, 1H), 6.85 (s, 1H), 6.95 (t,1H), 7.42 (t, 1H), 7.9 (d, 2H), 8.5 (s, 1H), 9.5 (s, 1H); Mass Spectrum:M+H⁺ 491.

EXAMPLE 17

[0938] Using an analogous procedure to that described in Example 16, theappropriate 4-chloroquinazoline was reacted with the appropriate anilinein the presence of hydrogen chloride to give the dihydrochloride salt ofeach of the compounds described in Table V, a portion of each of whichwas converted to the free base using an analogous procedure to that.described in Example 3. TABLE V

No. and Note (R¹)_(m) Q¹ (R²)_(n) [1] 7-methoxy N-methylpiperidin-4-yl2,4-dichloro [2] 7-methoxy N-methylpiperidin-4-yl 4-bromo-2-chloro [3]7-methoxy N-methylpiperidin-4-yl 2-chloro-4-cyano [4] 7-methoxyN-methylpiperidin-4-yl 2-bromo-4-fluoro [5] 7-methoxyN-methylpiperidin-4-yl 2-bromo-4-chloro [6] 7-methoxyN-methylpiperidin-4-yl 2,4-dibromo [7] 7-methoxy N-methylpiperidin-4-yl2-bromo [8] 7-methoxy N-methylpiperidin-4-yl 2-bromo-4-methyl [9]7-methoxy N-methylpiperidin-4-yl 2-fluoro-4-chloro [10] 7-methoxyN-methylpiperidin-4-yl 2-fluoro-4-bromo [11] 7-methoxyN-methylpiperidin-4-yl 2-fluoro-3-chloro [12] 7-methoxyN-methylpiperidin-4-yl 2,4-dimethoxy [13] 7-methoxyN-methylpiperidin-4-yl 2,3-dimethoxy [14] 7-methoxyN-methylpiperidin-4-yl 2-methoxy-5-methyl [15] 7-methoxyN-methylpiperidin-4-yl 2-methoxy-5-chloro [16] 7-methoxyN-methylpiperidin-4-yl 2-methoxy [17] 7-methoxy N-methylpiperidin-4-yl2-ethoxy [18] 7-methoxy N-methylpiperidin-4-yl 2-methylthio [19]7-methoxy N-methylpiperidin-4-yl 2-acetyl-4-chloro [20] 7-methoxyN-methylpiperidin-4-yl 2-methyl-5-chloro [21] 7-methoxyN-methylpiperidin-4-yl 2-methyl-3-chloro [22] 7-methoxyN-methylpiperidin-4-yl 2-methyl-4-chloro [23] 7-methoxyN-methylpiperidin-4-yl 2-methyl-5-methoxy [24] 7-methoxyN-methylpiperidin-4-yl 2-isopropenyl [25] 7-methoxyN-methylpiperidin-4-yl 2-(1-pyrrolyl) [26] 7-methoxyN-methylpiperidin-4-yl 2-piperidino [27] 7-(2-pyrrolidin-1-ylethoxy)cyclopentyl 2-bromo-5-methoxy [28] 7-(2-pyrrolidin-1-ylethoxy)cyclopentyl 5-methoxy- 2-pyrrolidin-1-yl [29]7-(2-pyrrolidin-1-ylethoxy) cyclopentyl 5-methoxy- 2-morpholinomethyl[30] 7-(2-pyrrolidin-1-ylethoxy) cyclopentyl 6-chloro-2,3-methylenedioxy [31] 7-methoxy piperidin-4-ylmethyl 6-chloro-2,3-methylenedioxy [32] 7-(2-pyrrolidin-1-ylethoxy) 4-tetrahydropyranyl6-chloro- 2,3-methylenedioxy [33] 7-(3-pyrrolidin-1-ylpropoxy)4-tetrahydropyranyl 6-chloro- 2,3-methylenedioxy [34] 7-benzyloxy4-tetrahydropyranyl 6-chloro- 2,3-methylenedioxy

[0939] Notes

[0940] [1] The free base gave the following data: NMR Spectrum: (CDCl₃)2.0-2.1 (m, 2H), 2.15-2.4 (m, 4H), 2.3 (s, 3H), 2.75-2.9 (m, 2H), 3.89(s, 3H), 4.55 (m, 1H), 6.5 (s, 1H), 6.82 (s, 1H), 7.28 (m, 1H), 7.42 (d,1H), 8.35 (d, 1H), 8.5 (s, 1H), 9.8 (s, 1H); Mass Spectrum: M+H⁺ 433 and435.

[0941] [2] The free base gave the following data: NMR Spectrum: (CDCl₃)1.95-2.1 (m, 2H), 2.15-2.35 (m, 4H), 2.3 (s, 3H), 2.7-2.9 (m, 2H), 3.9(s, 3H), 4.42-4.6 (m, 1H), 6.55 (d, 1H), 6.82 (d, 1H), 7.4 (m, 1H), 7.55(d, 1H), 8.3 (d, 1H), 8.51 (s, 1H), 9.8 (s, 1H); Mass Spectrum: M+H⁺ 477and 479.

[0942] [3] The free base gave the following data: NMR Spectrum: (CDCl₃)1.95-2.1 (m, 2H), 2.1-2.25 (m, 4H), 2.28 (s, 3H), 2.85 (br d, 2H), 3.9(s, 3H), 4.5 (m, 1H), 6.55 (d, 1H), 6.85 (d, 1H), 7.58 (m, 1H), 7.7 (s,1H), 8.6 (s, 1H), 8.82 (d, 1H); Mass Spectrum: M+H⁺ 424 and 426.

[0943] [4] The free base gave the following data: NMR Spectrum: (CDCl₃)2.0-2.1 (m, 2H), 2.15-2.4 (m, 4H), 2.28 (s, 3H), 2.8 (m, 2H), 3.9 (s,3H), 4.55 (m, 1H), 6.5 (s, 1H), 6.8 (s, 1H), 7.1 (m, 1H), 7.35 (m, 1H),8.05 (m, 1H), 8.48 (s, 1H), 9.55 (br s, 1H); Mass Spectrum: M+H⁺ 461 and463.

[0944] [5] The free base gave the following data: NMR Spectrum: (CDCl₃)2.0-2.15 (m, 2H), 2.2-2.4 (m, 4H), 2.3 (s, 3H), 2.8 (m, 2H), 3.9 (s,3H), 4.5-4.6 (m, 1H), 6.5 (d, 1H), 6.8 (d, 1H), 7.3 (m, 1H), 7.6 (d,1H), 8.15 (d, 1H), 8.5 (s, 1H), 9.6 (br s, 1H); Mass Spectrum: M+H⁺ 477and 479.

[0945] [6] The free base gave the following data: NMR Spectrum: (CDCl₃)2.0-2.2 (m, 2H), 2.2-2.35 (m, 4H), 2.25 (s, 3H), 2.7-2.9 (m, 2H), 3.9(s, 3H), 4.5-4.6 (m, 2H), 6.55 (s, 1H), 6.85 (s, 1H), 7.15 (m, 1H), 7.45(d, 1H), 8.45 (s, 1H), 8.55 (s, 1H), 9.68 (br s, 1H); Mass Spectrum:M+H⁺ 521, 523 and 525.

[0946] [7] The free base gave the following data: NMR Spectrum: (CDCl₃)2.0-2.15 (m, 2H), 2.15-2.38 (m, 4H), 2.3 (s, 3H), 2.8 (m, 2H), 3.9 (s,3H), 4.55 (m, 1H ), 6.5 (d, 1H), 6.82 (d, 1H), 7.02 (m, 1H), 7.35 (m,1H), 7.36 (d, 1H), 8.15 (d, 1H), 8.5 (s, 1H), 9.65 (s, 1H); MassSpectrum: M+H⁺ 443 and 445.

[0947] [8] The free base gave the following data: NM Spectrum: (CDCl₃)2.0-2.15 (m, 2H), 2.2-2.4 (m, 4H), 2.28 (s, 3H), 2.31 (s, 3H), 2.8 (m,2H), 3.89 (s, 3H), 4.55 (m, 1H), 6.5 (s, 1H), 6.8 (s, 1H), 7.15 (m, 1H),7.42 (s, 1H), 7.95 (d, 1H), 8.48 (s, 1H), 9.55 (s, 1H); Mass Spectrum:M+H⁺ 457 and 449.

[0948] [9] The free base gave the following data: NMR Spectrum: (CDCl₃)1.95-2.1 (m, 2H), 2.15-2.3 (m, 4H), 2.3 (s, 3H), 2.85 (d, 1H), 3.9 (s,3H), 4.5 (m, 1H), 6.5 (d, 1H), 6.82 (d, 1H), 7.1-7.2 (m, 2H), 8.58 (s,1H), 8.75 (m, 1H); Mass Spectrum: M+H⁺ 417 and 419.

[0949] [10] The free base gave the following data: NMR Spectrum: (CDCl₃)1.95-2.1 (m, 2H), 2.15-2.35 (m, 4H), 2.32 (s, 3H), 2.9 (m, 2H), 3.89 (s,3H), 4.55 (m, 1H), 6.5 (d, 1H), 6.85 (d, 1H), 7.25-7.35 (m, 2H), 8.58(s, 1H), 8.75 (m, 1H); Mass Spectrum: M+H⁺0 461 and 463.

[0950] [11] The free base gave the following data: NMR Spectrum: (CDCl₃)1.95-2.1 (m, 2H), 2.12-2.28 (m, 4H), 2.28 (s, 3H), 2.85 (m, 2H), 3.86(s, 3H), 4.5 (m, 1H), 6.5 (s, 1H), 6.8 (s, 1H), 7.0-7.1 (m, 2H), 8.55(s, 1H), 8.68 (m, 1H); Mass Spectrum: M+H⁺ 417 and 419.

[0951] [12] The free base gave the following data: NMR Spectrum: (CDCl₃)1.95-2.1 (m, 2H), 2.1-2.22 (m, 4H), 2.25 (s, 3H), 2.82 (m, 2H), 3.77 (s,3H), 3.83 (s, 3H), 3.85 (s, 3H), 4.48 (m, 1H), 6.45 (d, 1H), 6.52 (m,1H), 6.8 (m, 2H), 8.45 (d, 1H), 8.52 (s, 1H); Mass Spectrum: M+H⁺ 425.

[0952] [13] The free base gave the following data: NMR Spectrum: (CDCl₃)1.9-2.1 (m, 2H), 2.1-2.25 (m, 4H), 2.28 (s, 3H), 2.7-2.9 (m, 2H), 3.8(s, 3H), 3.85 (s, 3H), 3.9 (s, 3H), 4.5 (m, 1H), 6.45 (d, 1H), 6.5-6.6(m, 2H), 6.8 (d, 1H), 8.4 (d, 1H), 8.5 (s, 1H), 9.85 (s, 1H); MassSpectrum: M+H⁺ 425.

[0953] [14] The free base gave the following data: NMR Spectrum: (CDCl₃)1.95-2.1 (m, 2H), 2.15-2.3 (m, 4H), 2.27 (s, 3H), 2.3 (s, 3H), 2.85 (m,2H), 3.87 (s, 3H), 3.89 (s, 3H), 4.5 (m, 1H), 6.5 (s, 1H), 6.8-6.9 (m,3H), 8.45 (s, 1H), 8.55 (s, 1H); Mass Spectrum: M+H⁺ 409.

[0954] [15] The free base gave the following data: NMR Spectrum: (CDCl₃)1.95-2.1 (m, 2H), 2.15-2.3 (m, 4H), 2.3 (s, 3H), 2.85 (d, 2H), 3.89 (s,3H), 3.9 (s, 3H), 4.5 (m, 1H), 6.5 (d, 1H), 6.8 (m, 2H), 7.0 (m, 1H),8.6 (s, 1H), 8.85 (d, 1H); Mass Spectrum: M+H⁺ 429 and 431.

[0955] [16] The free base gave the following data: NMR Spectrum: (CDCl₃)2.0-2.1 (m, 2H), 2.15-2.3 (m, 4H), 2.29 (s, 3H), 2.85 (m, 2H), 3.88 (s,3H), 3.9 (s, 3H), 4.52 (m, 1H), 6.5 (s, 1H), 6.8 (s, 1H), 6.95 (m, 1H),7.02 (m, 2H), 8.55 (s, 1H), 8.65 (m, 1H); Mass Spectrum: M+H⁺ 395.

[0956] [17] The free base gave the following data: NMR Spectrum: (CDCl₃)1.4 (t, 3H), 1.9-2.1 (m, 2H), 2.1-2.3 (m, 4H), 2.24 (s, 3H), 2.7-2.9 (m,2H), 3.9 (s, 3H), 4.2 (q, 2H), 4.4-4.55 (m, 1H), 6.5 (d, 1H), 6.8 (d,1H), 6.9 (m, 1H), 6.95-7.1 (m, 2H), 8.38 (m, 1H), 8.5 (s, 1H), 9.85 (brs, 1H); Mass Spectrum: M+H⁺ 409.

[0957] [18] The free base gave the following data: NMR Spectrum: (CDCl₃)2.05-2.35 (m, 6H), 2.27 (s, 3H), 2.38 (s, 3H), 2.7-2.9 (m, 2H), 3.9 (s,3H), 4.5-4.6 (m, 1H), 6.5 (d, 1H), 6.8 (d, 1H), 7.15 (m, 1H), 7.26 (m,1H), 7.38 (m, 1H), 7.98 (d, 1H), 8.5 (s, 1H), 9.7 (br s, 1H); MassSpectrum: M+H⁺ 411.

[0958] [19] The free base gave the following data: NMR Spectrum: (CDCl₃)2.15-2.35 (m, 6H), 2.27 (s, 3H), 2.57 (s, 3H), 2.82 (m, 2H), 3.89 (s,3H), 4.55 (m, 1H), 6.52 (s, 1H), 6.8 (s, 1H), 7.48 (m, 1H), 7.75 (d,1H), 8.3 (d, 1H), 8.5 (s, 1H); Mass Spectrum: M+H⁺ 441 and 443.

[0959] [20] The free base gave the following data: NMR Spectrum: (CDCl₃)1.9-2.0 (m, 2H), 2.15-2.4 (m, 4H), 2.26 (s, 3H), 2.28 (s, 3H), 2.75 (brs, 2H), 3.9 (s, 3H), 4.55 (br s, 1H), 6.5 (d, 1H), 6.82 (s, 1H), 7.1 (m,1H), 7.18 (d, 1H), 7.8 (s, 1H), 8.48 (s, 1H), 9.1 (s, 1H); MassSpectrum: M+H⁺ 413 and 415.

[0960] [21] The free base gave the following data: NMR Spectrum: (CDCl₃)1.9-2.0 (m, 2H), 2.15-2.25 (m, 2H), 2.28 (s, 3H), 2.25-2.38 (m, 2H),2.35 (s, 3H), 2.7 (br s, 2H), 3.9 (s, 3H), 4.6 (m, 1H), 6.5 (d, 1H), 6.8(d, 1H), 7.18 (m, 1H), 7.28 (m, 1H), 7.5 (d, 1H), 8.45 (s, 1H), 9.35 (s,1H); Mass Spectrum: M+H⁺ 413 and 415.

[0961] [22] The free base gave the following data: NMR Spectrum: (CDCl₃)1.9-2.0 (m, 2H), 2.2-2.4 (m, 4H), 2.27 (s, 3H), 2.65-2.8 (m, 2H), 3.89(s, 3H), 4.55 (m, 1H), 6.5 (d, 1H), 6.8 (d, 1H), 7.15-7.25 (m, 2H), 7.6(d, 1H), 8.45 (s, 1H), 9.25 (s, 1H); Mass Spectrum: M+H⁺ 413 and 415.

[0962] [23] The free base gave the following data: NMR Spectrum: (CDCl₃)1.9-2.0 (m, 2H), 2.15-2.22 (m, 4H), 2.17 (s, 3H), 2.22 (s, 3H), 2.72 (m,2H), 3.78 (s, 3H), 3.89 (s, 3H), 4.55 (m, 1H), 6.5 (d, 1H), 6.7 (m, 1H),6.8 (d, 1H), 7.15 (d, 1H), 7.3 (d, 1H), 8.45 (s, 1H), 9.3 (s, 1H); MassSpectrum: M+H⁺ 409.

[0963] [24] The free base gave the following data: NMR Spectrum: (CDCl₃)1.85-2.0 (m, 2H), 2.05 (s, 3H), 2.1-2.3 (m, 4H), 2.28 (s, 3H), 2.72 (m,2H), 3.92 (s, 3H), 4.5 (m, 1H), 5.1 (s, 1H), 5.25 (s, 1H), 6.5 (s, 1H),6.82 (s, 1H), 7.2 (t, 1H), 7.3 (d, 1H), 7.35 (t, 1H), 7.85 (d, 1H), 8.5(s, 1H), 9.35 (s, 1H).

[0964] [25] The free base gave the following data: NMR Spectrum: (CDCl₃)1.45-1.6 (m, 2H), 1.8-1.95 (m, 2H), 2.05-2.2 (m, 2H), 2.2 (s, 3H),2.4-2.55 (br s, 2H), 3.95 (s, 3H), 4.25-4.35 (m, 2H), 6.25 (d, 2H), 6.4(s, 1H), 6.8 (s, 1H), 6.85 (d, 2H), 7.2 (m, 1H), 7.3 (m, 1H), 7.35 (m,1H), 8.05 (d, 1H), 8.5 (s, 1H), 9.25 (br s, 1H); Mass Spectrum: M+H⁺430.

[0965] [26] The free base gave the following data: NMR Spectrum: (CDCl₃)1.6 (m, 2H), 1.7 (m, 4H), 2.1 (m, 2H), 2.2 (s, 3H), 2.2 (m, 2H), 2.3 (m,2H), 2.7 (m, 2H), 2.9 (m, 4H), 3.95 (s, 3H), 4.6 (m, 1H), 6.1 (d, 1H),6.9 (d, 1H), 7.1-7.2 (m, 3H), 8.02 (m, 1H), 8.52 (s, 1H), 9.72 (s, 1H);Mass Spectrum: M+H⁺ 448.

[0966] [27] The free base gave the following data: NMR Spectrum: (CDCl₃)1.6-1.78,(m, 4H), 1.85 (m, 4H), 2.1 (m, 4H), 2.65 (m, 4H), 2.98 (m, 2H),3.82 (s, 3H), 4.25 (m, 2H), 5.02 (m, 1H), 6.4 (d, 1H), 6.45 (m, 1H),6.82 (d, 1H), 7.5 (d, 1H), 7.85 (d, 1H), 8.52 (s, 1H), 9.62 (s, 1H);Mass Spectrum: M+H⁺ 527 and 529.

[0967] The4-chloro-5-cyclopentyloxy-7-(2-pyrrolidin-1-ylethoxy)quinazoline used asa starting material was prepared as follows:

[0968] A mixture of 7-acetoxy4-chloro-5-cyclopentyloxyquinazoline (1 g),a saturated methanolic ammonia solution (10 ml) and methanol (10 ml) wasstirred at ambient temperature for 30 minutes. The mixture wasevaporated and the residue was triturated under water. The resultantsolid was isolated, washed with water and dried under vacuum to give4-chloro-5-cyclopentyloxy-7-hydroxyquinazoline (0.67 g); NMR Spectrum:(DMSOd₆) 1.6-1.75 (m, 2H), 1.75-1.85 (m, 2H), 1.85-2.05 (m, 4H), 5.0 (m,1H), 6.72 (d, 1H), 6.8 (d, 1H), 8.7 (s, 1H); Mass Spectrum: M+H⁺ 265.

[0969] Using an analogous procedure to that described in Example 1,4-chloro-5-cyclopentyloxy-7-hydroquinazoline (0.84 g) was reacted with2-pyrrolidin-1-ylethanol (0.448 ml). There was thus obtained4-chloro-5-cyclopentyloxy-7-(2-pyrrolidin-1-ylethoxy)quinazoline (0.82g); NMR Spectrum: (CDCl₃) 1.65-2.12 (m, 12H), 2.65 (m, 4H), 2.97 (m,2H), 4.25 (m, 2H), 4.9 (m, 1H), 6.65 (d, 1H), 6.92 (d, 1H), 8.8 (s, 1H);Mass Spectrum: M+H⁺ 362 and 364.

[0970] [28] The reaction product was purified by column chromatographyon reversed phase silica using decreasingly polar mixtures of water,acetonitrile and a saturated methanolic ammonia solution as eluent. Thefree base gave the following data: NMR Spectrum: (CDCl₃) 1.6-1.75 (m,2H), 1.8 (m, 2H), 1.8-1.95 (m, 8H), 2.05 (m, 4H), 2.65 (br s, 1H), 2.95(m, 2H), 3.05 (br s, 4H), 3.8 (s, 3H), 4.25 (m, 2H), 4.95 (m, 1H), 6.55(s, 1H), 6.65 (m, 1H), 6.8 (s, 1H), 7.1 (d, 1H), 7.75 (d, 1H), 8.5 (s,1H), 9.7 (s, 1H); Mass Spectrum: M+H⁺ 518.

[0971] [29] The free base gave the following data: NMR Spectrum: (CDCl₃)1.65-1.9 (m, 8g), 1.9-2.15 (m, 4H), 2.35 (m, 4H), 2.65 (m, 4H), 2.98 (m,2H), 3.42 (s, 2H), 3.55 (m, 4H), 3.82 (s, 3H), 4.25 (m, 2H), 5.0 (m,1H), 6.6 (s, 1H), 6.8 (m, 2H), 7.1 (s, 1H), 7.38 (d, 1H), 8.42 (s, 1H),9.3 (s, 1H); Mass Spectrum: M+H⁺ 548.

[0972] The 2-morpholinomethyl-5-methoxyaniline used as a startingmaterial was prepared as follows:

[0973] A mixture of 4-methoxy-2-nitrotoluene (20 g), N-bromosuccinimide(23 g), a catalytic amount of benzoyl peroxide and carbon tetrachloride(100 ml) was heated to reflux for 8 hours. The mixture was diluted withmethylene chloride (200 ml) and washed in turn with a 2N aqueous sodiumhydroxide solution and brine. The organic layer was dried over magnesiumsulphate and evaporated. There was thus obtained 4-methoxy-2-nitrobenzylbromide (29 g) which was used without further purification.

[0974] Morpholine (2.8 ml) was added to a stirred solution of4-methoxy-2-nitrobenzyl bromide (4 g) in diethyl ether (150 ml) whichwas cooled to 0°C. The resultant mixture was stirred at ambienttemperature for 16 hours. The mixture was filtered and the filtrate wasevaporated. There was thus obtained2-morpholinomethyl-5-methoxy-1-nitrobenzene (4 g); NMR Spectrum: (CDCl₃)2.4 (m, 4H), 3.68 (m, 4H), 3.7 (s, 2H), 3.88 (s, 3H), 7.1 (m, 1H), 7.35(d, 1H), 7.45 (d, 1H).

[0975] A mixture of the material so obtained, 10% palladium on charcoalcatalyst (0.2 g) and methanol (100 ml) was stirred under an atmospherepressure of hydrogen for 1 hour. The mixture was filtered and thefiltrate was evaporated. The residue was purified by columnchromatography on silica using a 49:1 mixture of methylene chloride andmethanol as eluent. There was thus obtained2-morpholinomethyl-5-methoxyaniline (1.9 g); NMR Spectrum: (CDCl₃) 2.4(br s, 4H), 3.48 (s, 2H), 3.7 (m, 4H), 3.78 (s, 3H), 4.75 (br s, 2H),6.2 (s, 1H), 6.25 (d, 1H), 6.9 (d, 1H).

[0976] [30] The free base gave the following data: NMR Spectrum: (CDCl₃)1.7-1.8 (m, 2H), 1.9 (br s, 4H), 2.1 (m, 2H), 2.65 (br s, 4H), 3.0 (brs, 2H), 4.25 (m, 2H), 5.0 (m, 1H), 6.05 (s, 1H), 6.55 (d, 1H), 6.7 (d,1H), 6.8 (d, 1H), 6.98 (d, 1H), 8.5 (s, 1H), 9.3 (s, 1H); Mass Spectrum:M+H⁺ 497 and 499.

[0977] The 6-chloro-2,3-methylenedioxyaniline used as a startingmaterial was prepared as follows:

[0978] Sulphuryl chloride (72.5 ml) was added dropwise during 1.7 hoursto a stirred mixture of benzodioxole (100 e), aluminium trichloride(0.43 g) and diphenyl sulphide (0.55 ml). Once the reaction started withthe evolution of sulphur dioxide, the reaction mixture was cooled in awater bath to a temperature of approximately 22° C. After completion ofthe addition. the reaction mixture was stirred at ambient temperaturefor 45 minutes. The reaction mixture was degassed under vacuum andfiltered and the filtrate was distilled at atmospheric pressure using aVigreux distillation column. There was thus obtained5-chloro-1,3-benzodioxole; b.p. 185-187° C.; NMR Spectrum: (CDCl₃) 6.0(s, 2H); 6.7 (d, 1H); 6.75-6.9 (m, 2H).

[0979] A mixture of diisopropylamine (4.92 ml) and THF (100 ml) wascooled to −78° C. and n-butyllithium (2.5 M in hexane, 14 ml) was addeddropwise. The mixture was stirred at −78° C. for 15 minutes.5-Chloro-1,3-benzodioxole (3.73 ml) was added dropwise and the reactionmixture was stirred at −78° C. for 30 minutes. Dry carbon dioxide gaswas bubbled into the reaction mixture for 30 minutes. The resultantreaction mixture was allowed to warm to/ambient temperature and wasstirred for a further hour. Water was added and the organic solvent wasevaporated. The residue was acidified to pH2 by the addition of 2Naqueous hydrochloric acid solution. The resultant solid was isolated andwashed in turn with water and diethyl ether. There was thus obtained5-chloro-1,3-benzodioxole-4-carboxylic acid (5.4 g); NMR Spectrum:(DMSOd₆) 6.15 (s, 2H), 7.0 (m, 2H), 13.7 (br s, 1H).

[0980] A portion (1 g) of the material so obtained was dissolved in1,4-dioxane (15 ml) and anhydrous tert-butanol (4 ml),diphenylphosphoryl azide (1.12 ml) and triethylamine (0.73 ml) wereadded in turn. The resultant mixture was stirred and heated to 100° C.for 4 hours. The mixture was evaporated and the residue was partitionedbetween ethyl acetate and a 5% aqueous citric acid solution. The organicphase was washed in turn with water, a saturated aqueous sodiumbicarbonate solution and brine, dried over magnesium sulphate andevaporated. The residue was purified by column chromatography on silicausing a 9:1 mixture of petroleum ether (b.p. 40-60° C.) and ethylacetate as eluent. There was thus obtained tert-butyl5-chloro-1,3-benzodioxol-4-ylcarbamate (1.1 g); NMR Spectrum: (DMSOd₆)1.45 (s, 9H), 6.1 (s, 2H), 6.85 (d, 1H), 6.95 (d, 1H), 8.75 (s, 1H).

[0981] A mixture of the material so obtained (1.1 g), trifluoroaceticacid (6 ml) and methylene chloride (20 ml) was stirred at ambienttemperature for 3 hours. The solvent was evaporated and the residue waspartitioned between ethyl acetate and a saturated aqueous sodiumbicarbonate solution. The organic phase was washed with brine, driedover magnesium sulphate and evaporated. There was thus obtained6-chloro-2,3-methylenedioxyaniline (0.642 g); NMR Spectrum: (DMSOd₆)5.15 (s, 2H), 6.0 (s, 2H), 6.25 (d, 1H), 6.75 (d, 1H).

[0982] [31] The reactants were5-[N-(tert-butoxycarbonyl)piperidin-1-ylmethoxy]-4-chloro-7-methoxyquinazoline(0.4 g) and 6-chloro-(2,3-methylenedioxy)aniline (0.089 g). Afterbasification and purification by column chromatography, the reactionproduct was suspended in a 2M solution of hydrogen chloride in diethylether (15 ml) and stirred at ambient temperature for 3 hours. Theresultant solid was isolated, washed with diethyl ether and dried undervacuum. The dihydrochloride salt so obtained gave the following data:NMR Spectrum: (DMSOd₆) 1.4-1.6 (m, 2H), 1.95 (d, 2H), 2.3-2.4 (m, 1H),2.8-2.9 (m, 2H), 3.3 (m, 2H), 3.97 (s, 3H), 4.4 (d, 2H), 6.12 (s, 2H),6.95 (d, 1H), 7.03 (d, 1H), 7.07 (d, 1H), 7.11 (d, 1H), 8.74 (s, 1H),8.8-9.0 (m, 2H), 10.25 (br s, 1H); Mass Spectrum: M+H⁺ 443 and 445.

[0983] [32] The free base gave the following data: NMR Spectrum: (CDCl₃)1.8-1.9 (m, 4H), 1.9-2.05 (m, 2H), 2.2-2.3 (m, 2H), 2.6-2.7 (m, 4H),2.95 (m, 2H), 3.6-3.7 (m, 2H), 4.05 (m, 2H), 4.25 (m, 2H), 4.75 (m, 1H),6.05 (s, 2H), 6.6 (d, 1H), 6.71 (d, 1H), 6.84 (d, 1H), 6.97 (d, 1H), 8.5(s, 1H), 9.3 (s, 1H); Mass Spectrum: M+H⁺ 513 and 515.

[0984] The4-chloro-7-(2-pyrrolidin-1-ylethoxy)-5-tetrahydropyran-4-yloxyquinazolineused as a starting material is described in Note [6] in Example 19.

[0985] [33] The free base gave the following data: NMR Spectrum: (CDCl₃)1.75-1.9 (m, 4H), 1.9-2.15 (m, 4H), 2.2-2.3 (m, 2H), 2.55 (br s, 4H),2.65 (m, 2H), 3.65 (m, 2H), 4.02 (m, 2H), 4.15 (m, 2H), 4.8 (m, 1H),6.05 (s, 2H), 6.52 (d, 1H), 6.72 (d, 1H), 6.82 (d, 1H), 6.97 (d, 1H),8.5 (s, 1H), 9.26 (s, 1H); Mass Spectrum: M+H⁺ 527 and 529.

[0986] The4-chloro-7-(3-pyrrolidin-1-ylpropoxy)-5-tetrahydropyran-4-yloxyquinazolineused as a starting material was prepared as follows:

[0987] Using an analogous procedure to that described in Note [6] belowExample 19, 4-chloro-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline(0.112 g) was reacted with 1-(3-hydroxypropyl)pyrrolidine (0.062 g) togive4-chloro-7-(3-pyrrolidin-1-ylpropoxy)-5-tetrahydropyran-4-yloxyquinazoline(0.125 g); NMR Spectrum: (CDCl₃) 1.7-1.9 (m, 4H), 1.95-2.2 (m, 6H), 2.55(br s, 4H), 2.65 (m, 2H), 3.65-3.75 (m, 2H), 4.0-4.1 (m, 2H), 4.2 (m,2H), 4.75 (m, 1H), 6.6 (d, 1H), 6.95 (d, 1H), 8.8 (s, 1H); MassSpectrum: M+H⁺ 392 and 394.

[0988] [34] The free base gave the following data: NMR Spectrum: (CDCl₃)2.1-2.2 (m, 2H), 2.15-2.3 (m, 2H), 3.52-3.65 (m, 2H), 3.95-4.08 (m, 2H),4.75 (m, 1H), 5.18 (s, 2H), 6.05 (s, 2H), 6.6 (d, 1H), 6.75 (d, 1H),6.9-7.0 (m, 2H), 7.3-7.5 (m, 5H), 8.55 (s, 1H), 9.34 (s, 1H); MassSpectrum: M+H⁺ 506 and 508.

[0989] The 7-benzyloxy-4-chloro-5-tetrahydropyran-4-yloxyquinazolineused as a starting material was prepared as follows:

[0990] Di-tert-butyl azodicarboxylate (16.3 g) was added portionwise toa stirred mixture of7-benzyloxy-5-hydroxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one(17 g), 4-hydroxytetrahydropyran (5.4 g) and methylene chloride (200 ml)that had been cooled to 5° C. The mixture was allowed to warm to ambienttemperature and was stirred for 2 hours. The mixture was evaporated andthe residue was dissolved in a saturated methanolic ammonia solution.The resultant mixture was stirred at ambient temperature for 16 hours.The mixture was evaporated and the residue was triturated under diethylether. The solid so obtained was dried under vaccuum to give7-benzyloxy-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (12.5g); NMR Spectrum: (DMSOd₆) 1.6-1.7 (m, 2H), 1.85-1.95 (m, 2H), 3.5 (m,2H), 3.9 (m, 2H), 4.75 (m, 1H), 5.22 (s, 2H), 6.7 (d, 1H), 6.8 (d, 1H),7.3-7.5 (m, 5H), 7.9 (s, 1H); Mass Spectrum: M+H⁺ 353.

[0991] A mixture of7-benzyloxy-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (9 g),phosphoryl chloride (2.8 ml), di-isopropylethylamine (11.4 ml) and1,2-dichloroethane (130 ml) was stirred and heated to 80° C. for 3hours. The mixture was evaporated to give7-benzyloxy-4-chloro-5-tetrahydropyran-4-yloxyquinazoline which was usedwithout further purification.

EXAMPLE 184-(2,6-dichloroanilino)-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazolinedihydrochloride

[0992] Sodium hexamethyldisilazane (1M solution in THF; 0.65 ml) wasadded to a solution of 2,6-dichloroaniline (0.105 g) in DMF (3 ml) andthe mixture was stirred at ambient temperature for 5 minutes. A solutionof 4-chloro-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline (0.1 g)in DMF (8 ml) was added and the mixture was stirred at ambienttemperature for 1 hour. A saturated aqueous ammonium chloride solutionwas added and the mixture was extracted with ethyl acetate. The organiclayer was evaporated and the residue was purified by columnchromatography on silica using as eluent a 9:10:1 mixture of methylenechloride, ethyl acetate and methanol followed by a 9:10:1 mixture ofmethylene chloride, ethyl acetate and a saturated methanolic ammoniasolution. The material so obtained was triturated under diethyl ether.The solid was isolated and dried under vacuum. The material so obtainedwas dissolved in a mixture of isopropanol (2 ml) and diethyl ether (2ml) and 6M hydrogen chloride in isopropanol (0.11 ml) was added. Themixture was evaporated and the residual solid was dried under vacuum.There was thus obtained the title compound as a dihydrochloride salt(0.06 g), a portion of which was converted into the free base using ananalogous procedure to that described in Example 3. The free base gavethe following characterising data: NMR Spectrum: (CDCl₃) 2.0-2.1 (m,2H), 2.15-2.25 (m, 2H), 2.3 (s, 3H), 2.4 (m, 2H), 2.68 (m, 2H), 3.95 (s,3H), 4.65 (m, 1H), 6.55 (d, 1H), 6.85 (d, 1H), 7.22 (m, 1H), 7.45 (d,2H), 8.5 (s, 1H), 9.3 (s, 1H); Mass Spectrum: M+H⁺ 433 and 435.

EXAMPLE 19

[0993] Using an analogous procedure to that described in Example 18, theappropriate 4-chloroquinazoline was reacted with the appropriate anilinein the presence of sodium hexamethyldisilazane to give the compoundsdescribed in Table VI. Each product was purified by way of itsdihydrochlolide salt and, unless otherwise stated, a portion of eachcompound was converted to the free base using an analogous procedure tothat described in Example 3. TABLE VI

No. & Note (R¹)_(m) Q¹ (R²)_(n) [1] 7-methoxy N-methylpiperidin-4-yl2-bromo-4-chloro- 6-fluoro [2] 7-methoxy N-methylpiperidin-4-yl4-chloro-2-trifluoromethyl [3] 7-methoxy N-methylpiperidin-4-yl4-cyano-2-trifluoromethyl [4] 7-(2-pyrroldin-1-ylethoxy) cyclopentyl2-bromo-4-chloro- 6-fluoro [5] 7-(2-pyrrolidin-1-ylethoxy) cyclopentyl4-chloro-2-trifluoromethyl [6] 7-(2-pyrrolidin-1-ylethoxy)4-tetrahydropyranyl 4-chloro-2-trifluoromethyl [7]7-(2-pyrrolidin-1-ylethoxy) 4-tetrahydropyranyl 2-bromo-4-chloro-6-fluoro

[0994] Notes

[0995] [1] The free base gave the following data: NMR Spectrum: (CDCl₃)1.98-2.1 (m, 2H), 2.22 (m, 2H), 2.31 (s, 3H), 2.4 (m, 2H), 2.7 (br s,2H), 3.95 (s, 3H), 4.65 (m, 1H), 6.55 (d, 1H), 6.85 (d, 1H), 7.25 (m,1H), 7.52 (d, 1H), 8.48 (s, 1H), 9.15 (s, 1H); Mass Spectrum: M+H⁺ 495,497 and 499.

[0996] [2] The free base gave the following data: NMR Spectrum: (CDCl₃)1.82-2.05 (m, 2H), 2.1-2.3 (m, 4H), 2.25 (s, 3H), 2.75 (m, 2H), 3.9 (s,3H), 4.5 (m, 1H), 6.5 (d, 1H), 6.8 (d, 1H), 7.55 (m, 1H), 7.65 (d, 1H),7.82 (d, 1H), 8.4 (s, 1H), 9.5 (s, 1H); Mass Spectrum: M+H⁺ 467 and 469.

[0997] [3] The free base gave the following data: N Spectrum: (CDCl₃)1.9-2.0 (m, 2H), 15 2.15-2.25 (m, 4H), 2.3 (s, 3H), 2.85 (br s, 2H),3.85 (s, 3H), 4.55 (m, 1H), 6.6 (d, 1H), 6.9 (d, 1H), 7.88 (m, 1H), 8.0(s, 1H), 8.3 (d, 1H), 8.52 (s, 1H), 9.78 (s, 1H); Mass Spectrum: M+H⁺458.

[0998] [4] The free base gave the following data: N Spectrum: (CDCl₃)1.7-1.95 (m, 8H), 2.05 (br s, 4H), 2.65 (br s, 4H), 2.95 (m, 2H), 4.25(m, 2H), 5.02 (m, 1H), 6.6 (s, 1H), 6.85 (s, 1H), 7.2 (m, 1H), 7.5 (s,1H), 8.45 (s, 1H), 9.1 (s, 1H); Mass Spectrum: M+H⁺ 549 and 551.

[0999] [5] The free base gave the following data: NMR Spectrum: (CDCl₃)1.5-1.75 (m, 2H), 1.75-1.9 (m, 6H), 1.9-2.05 (m, 2H), 2.05-2.15 (m, 2H),2.62 (br s, 4H), 2.98 (m, 2H), 4.25 (m, 2H), 4.98 (m, 1H), 6.6 (s, 1H),6.85 (s, 1H), 7.55 (m, 1H), 7.65 (d, 1H), 7.85 (d, 1H), 8.45 (s, 1H),9.45 (s, 1H); Mass Spectrum: M+H⁺ 521 and 523.

[1000] [6] The dihydrochloride salt gave the following data: NMRSpectrum: (DMSOd₆ and CF₃CO₂D) 1.8-2.2 (m, 8H), 3.1-3.3 (m, 2H), 3.5 (t,2H), 3.6-3.75 (m, 4H), 3.95 (d, 2H), 4.6 (t, 2H), 5.1 (m, 1H), 7.0 (d,1H), 7.2 (d, 1H), 7.75 (d, 1H), 7.95 (m, 1H), 8.0 (d, 1H), 8.8 (s, 1H);Mass Spectrum: M+H⁺ 537 and 539.

[1001] The4-chloro-7-(2-pyrrolidin-1-ylethoxy)-5-tetrahydropyran-4-yloxyquinazolineused as a starting material was prepared as follows:

[1002] Di-tert-butyl azodicarboxylate (0.99 g) was added to a stirredmixture of 4-chloro-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline (0.75g), triphenylphosphine (1.14 g), 1-(2-hydroxyethyl)pyrrolidine (0.372 g)and methylene chloride (20 ml) and the mixture was stirred at ambienttemperature for 0.5 hours. The mixture was poured onto a column ofsilica and eluted initially with a 49:1 mixture of methylene chlorideand methanol followed by a 97:3 mixture of methylene chloride and asaturated methanolic ammonia solution. There was thus obtained4-choro-7-(2-pyrrolidin-1-ylethoxy)-5-tetrahydropyran-4-yloxyquinazoline(0.9 g); NMR Spectrum: (CDCl₃) 1.8-1.9 (m, 4H), 1.9-2.05 (m, 2H),2.1-2.2 (m, 2H), 2.6-2.7 (m, 4H), 2.97 (m, 2H), 3.65-3.75 (m, 2H),4.0-4.1 (m, 2H), 4.25 (m, 2H), 4.75 (m, 1H), 6.7 (d, 1H), 6.96 (d, 1H),9.81 (s, 1H); Mass Spectrum: M+H⁺ 378 and 380.

[1003] [7] The dihydrochloride salt gave the following data: NMRSpectrum: (DMSOd₆ and CF₃CO₂D) 1.85-2.2 (m, 8H), 3.15-3.25 (m, 2H),3.5-3.65 (m, 2H), 3.65-3.75 (m, 4H), 4.0 (m, 2H), 4.6 (t, 2H), 5.15 (m,1H), 7.0 (d, 1H), 7.22 (d, 1H), 7.73 (m, 1H), 7.87 (d, 1H), 8.88 (s,1H); Mass Spectrum: M+H⁺ 565 and 567.

EXAMPLE 204-(2-bromo-5-methoxyanilino)-7-hydroxy-5-piperidin-4-yloxyquinazoline

[1004] A mixture of7-benzyloxy4-(2-bromo-5-methoxyanilino)-5-piperidin-4-yloxyquinazoline(0.35 g) and trifluoroacetic acid (6 ml) was stirred and heated to 80°C. for 5 hours. The mixture was evaporated and the residue was dissolvedin water (12 ml). The solution was basified to pH8 by the addition ofsodium bicarbonate. The resultant precipitate was isolated, washed withwater and with ethyl acetate and dried under vacuum. There was thusobtained the title compound (0.26 g); NMR Spectrum: (DMSOd₆) 1.95-2.15(m, 2H), 2.32 (d, 2H), 3.05 (t, 2H), 3.3-3.4 (m, 2H), 3.8 (s, 3H), 5.0(m, 1H), 6.75 (m, 2H), 6.85 (s, 1H), 7.6 (d, 1H), 7.98 (s, 1H), 8.4 (s,1H), 9.58 (s, 1H); Mass Spectrum: M+H⁺ 445 and 447.

EXAMPLE 214-(2-chloro-5-methoxyanilino)-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline

[1005] Using an analogous procedure to that described in Example 20,7-benzyloxy-4-(2-chloro-5-methoxyanilino)-5-tetrahydropyran-4-yloxyquinazoline(0.78 g) was reacted with trifluoroacetic acid (5 ml). The reactionmixture was evaporated and the residue was triturated under diethylether. The precipitate was isolated and the solid was dissolved in amixture of methylene chloride and a saturated methanolic ammoniasolution. The mixture was evaporated and the residue was purified bycolumn chromatography on silica using a 97:3 mixture of methylenechloride and methanol as eluent. There was thus obtained the titlecompound (0.47 g); NMR Spectrum: (DMSOd₆) 1.8-1.9 (m, 2H), 2.2 (d, 2H),3.52 (t, 2H), 3.8 (s, 3H), 3.92 (m, 2H), 4.95 (m, 1H), 6.7 (s, 1H),6.75-6.85 (m, 2H), 7.5 (d, 1H), 8.12 (d, 1H), 8.4 (s, 1H), 9.85 (s, 1H);Mass Spectrum: M+H⁺ 402 and 404.

EXAMPLE 224-(2-chloro-5-methoxyanilino)-7-[(2R)-2-hydroxy-3-morpholinopropoxy]-5-tetrahydropyran-4-yloxyquinazoline

[1006] A mixture of4-(2-chloro-5-methoxyanilino)-7-[(2R)-2,3-epoxypropoxy]-5-tetrahydropyran-4-yloxyquinazoline(0.08 g), morpholine (0.044 ml), ethanol (1 ml) and chloroform (1 ml)was stirred and heated to 45° C. for 16 hours. The mixture was cooled toambient temperature and evaporated. The residue was triturated underpentane. The resultant solid was isolated, washed with diethyl ether anddried under vacuum to give the title compound (0.08 g); NMR Spectrum:(DMSOd₆ and CF₃CO₂D) 1.9-2.05 (m, 2H), 2.15 (d, 2H), 3.1-3.45 (m, 5H),3.45-3.6 (m, 3H), 3.7-3.9 (m, 2H), 3.8 (s, 3H), 3.9-4.1 (m, 2H), 4.22(m, 1H), 4.45 (m, 1H), 5.15 (m, 1H), 6.95 (s, 1H), 7.02 (m, 1H), 7.15(s, 1H), 7.5-7.6 (m, 2H), 8.9 (s, 1H); Mass Spectrum: M+H⁺ 545 and 547.

[1007] The4-(2-chloro-5-methoxyanilino)-7-[(2R)-2,3-epoxypropoxy]-5-tetrahydropyran-4-yloxyquinazolineused as a starting material was prepared as follows:

[1008] Caesium fluoride (0.213 g) and (2R)-(−)-glycidyl tosylate (0.119g) were added in turn to a solution of4-(2-chloro-5-methoxyanilino)-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline(0.19 g) in DMA (2 ml) and the reaction mixture was stirred and heatedto 50° C. for 4.5 hours. The mixture was evaporated and the residue waspartitioned between ethyl acetate and a saturated aqueous sodiumbicarbonate solution. The organic layer was washed with water and withbrine, dried over magnesium sulphate and evaporated. The residue waspurified by column chromatography on silica using a 49:1 mixture ofmethylene chloride and methanol as eluent. There was thus obtained4-(2-chloro-5-methoxyanilino)-7-[(2R)-2,3-epoxypropoxy]-5-tetrahydropyran-4-yloxyquinazoline(0.155 g); NMR Spectrum: (CDCl₃) 2.0-2.1 (m, 2H), 2.25 (d, 2H), 2.8 (m,1H), 2.98 (m, 1H), 3.45 (br s, 1H), 3.6 (t, 2H), 3.85 (s, 3H), 3.95-4.1(m, 3H), 4.45 (m, 1H), 4.75 (m, 1H), 6.6-6.7 (m, 2H), 6.85 (s, 1H), 7.32(d, 1H), 8.2 (d, 1H), 8.6 (s, 1H), 9.85 (s, 1H); Mass Spectrum: M+H⁺ 458and 460.

EXAMPLE 234-(2-chloro-5-methoxyanilino)-7-[(2R)-2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazoline

[1009] Using an analogous procedure to that described in Example 22,4-(2-chloro-5-methoxyanilino)-7-[(2R)-2,3-epoxypropoxy]-5-tetrahydropyran-4-yloxyquinazohne(0.07 g) was reacted with 1-methylpiperazine (0.05 ml) to give the titlecompound (0.04 g); NMR Spectrum: (DMSOd₆) 1.8-1.9 (m, 2H), 2.2 (s, 3H),2.2 (d, 2H), 2.25-2.6 (m, 10H), 3.55 (t, 2H), 3.8 (s, 3H), 3.92 (m, 2H),4.05 (m, 2H), 4.2 (m, 1H), 4.9 (d, 1H), 5.1 (m, 1H), 6.8 (m, 1H), 6.85(d, 1H), 6.95 (d, 1H), 7.5 (d, 1H), 8.12 (d, 1H), 8.5 (s, 1H), 9.9 (s,1H); Mass Spectrum: M+H⁺ 558 and 560.

EXAMPLE 244-(2-bromo-5-methoxyanilino)-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline

[1010] A mixture of7-acetoxy-4-chloro-5-tetrahydropyran-4-yloxyquinazoline (1.7 g),2-bromo-5-methoxy aniline (1.1 g) and isopropanol (10 ml) was stirredand heated to 80° C. for 1 hour. The resultant precipitate was isolated,washed with isopropanol and dried under vacuum to give7-acetoxy-4-(2-bromo-5-methoxyanilino)-5-tetrahydropyran-4-yloxyquinazolinehydrochloride (2 g); NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 1.9-2.1 (m, 2H),2.17 (d, 2H), 2.38 (s, 3H), 3.5 (t, 2H), 3.8 (s, 3H), 3.95 (m, 2H), 5.1(m, 1H), 7.0 (m, 1H), 7.32 (s, 1H), 7.42 (d, 1H), 7.5 (s, 1H), 7.7 (d,1H), 8.9 (s, 1H); Mass Spectrum: M+H⁺ 488 and 490.

[1011] A mixture of a portion (0.15 g) of the material so obtained and asaturated methanolic ammonia solution (5 ml) was stirred at ambienttemperature for 16 hours. The mixture was evaporated and the residue wastriturated under water. The resultant solid was isolated and dried undervacuum to give the title compound (0.091 g); NMR Spectrum: (DMSOd₆)1.8-2.0 (m, 2H), 2.15 (d, 2H), 3.52 (t, 2H), 3.8 (s, 3H), 3.9 (m, 2H),4.95 (m, 1H), 6.7 (s, 1H), 6.75 (m, 1H), 6.8 (d, 1H), 7.6 (d, 1H), 7.85(d, 1H), 8.35 (s, 1H), 9.65 (s, 1H), 10.58 (s, 1H); Mass Spectrum: M+H⁺446 and 448.

[1012] The 7-acetoxy-4-chloro-5-tetrahydropyran-4-yloxyquinazoline usedas a starting material was prepared as follows:

[1013] A solution of7-acetoxy-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (1.52 g)in 1,2-dichloroethane (30 ml) containing phosphorus oxychloride (0.51ml) and di-isopropylethylamine (2.17 ml) was stirred and heated to 80°C. for 2 hours. The mixture was evaporated to give the required materialwhich was used without further purification.

EXAMPLE 254-(2-chloro-5-methoxyanilino)-7-hydroxy-5-tetrahydrofuran-3-yloxyquinazoline

[1014] Using an analogous procedure to that described in Example 20,7-benzyloxy-4-(2-chloro-5-methoxyanilino)-5-tetrahydrofuran-3-yloxyquinazoline(0.39 g) was reacted with trifluoroacetic acid (2.5 ml). The reactionmixture was evaporated and the residue was triturated under diethylether. The precipitate was isolated and the solid was dissolved in amixture of methylene chloride and a saturated methanolic ammoniasolution. The mixture was evaporated and the residue was purified bycolumn chromatography on silica using a 97:3 mixture of methylenechloride and methanol as eluent. There was thus obtained the titlecompound (0.47 g); NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 2.2-2.3 (m, 1H),2.3-2.5 (m, 1H), 3.8 (s, 3H), 3.75-3.9 (m, 1H), 3.9-4.0 (m, 2H), 4.2 (d,1H), 5.5 (m, 1H), 6.8 (s, 1H), 6.92 (s, 1H), 7.02 (m, 1H), 7.55 (d, 1H),7.6 (d, 1H), 8.85 (s, 1H); Mass Spectrum: M+H⁺ 388 and 390.

EXAMPLE 264-(2-chloro-5-methoxyanilino)-7-hydroxy-5-isopropoxyquinazoline

[1015] Using an analogous procedure to that described in Example 20,7-benzyloxy-4-(2-chloro-5-methoxyanlino)-5-isopropoxyquinazoline (0.33g) was reacted with trifluoroacetic acid. There was thus obtained thetitle compound (0.17 g); NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 1.55 (d,6H), 3.85 (s, 3H), 5.1 (m, 1H), 6.8 (s, 1H), 6.92 (s, 1H), 7.0 (m, 1H),7.58 (d, 1H), 7.65 (d, 1H), 8.85 (s, 1H); Mass Spectrum: M+H⁺ 360 and362.

EXAMPLE 274-(benzofuran-7-ylamino)-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazolinedihydrochloride

[1016] Using an analogous procedure to that described in Example 5,4-chloro-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline was reactedwith 7-aminobenzofuran to give the title compound, a portion of whichwas treated with a saturated methanolic ammonia solution. The mixturewas filtered and the filtrate was evaporated to give the free base; NMRSpectrum: (CDCl₃) 2.15-2.35 (m, 6H), 2.32 (s, 3H), 2.92 (m, 2H), 3.9 (s,3H), 4.6 (m, 1H), 6.5 (d, 1H), 6.8 (d, 1H), 6.85 (d, 1H), 7.25-7.4 (m,2H), 7.68 (d, 1H),8.58 (d, 1H), 8.6 (s, 1H), 10.25 (br s, 1H); MassSpectrum: M+H⁺ 405.

[1017] The 7-aminobenzofuran used as a starting material was prepared asfollows

[1018] Hydrazine hydrate (0.45 ml) was added dropwise to a stirredmixture of 7-nitrobenzofuran (J. Med. Chem., 1988, 31, 1934; 0.5 g),Raney nickel (0.02 g) and methanol (9 ml) that had been warmed to 55° C.The resultant mixture was heated to reflux for 30 minutes. The catalystwas removed by filtration and the filtrate was evaporated. The residuewas partitioned between methylene chloride and water. The organic phasewas dried over magnesium sulphate and evaporated to give7-aminobenzofuran (0.4 g) as an oil; NMR Spectrum: (DMSOd₆) 5.25 (br s,2H), 6.55 (d, 1H), 6.8 (m, 2H), 6.9 (t, 1H), 7.85 (d, 1H).

EXAMPLE 284-(3-chlorobenzofuran-7-ylamino)-7-[3-(4-methylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazolinedihydrochloride

[1019] Using an analogous procedure to that described in Example 5,4-chloro-7-[3-(4-methylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazolinewas reacted with 7-amino-3-chlorobenzofuran to give the title compound,a portion of which was treated with a saturated methanolic ammoniasolution. The mixture was filtered and the filtrate was evaporated togive the free base; NMR Spectrum: (CDCl₃) 2.07 (m, 2H), 2.1 (m, 2H),2.25 (m, 2H), 2.27 (s, 3H), 2.35-2.68 (m, 10H), 3.6 (t, 2H), 4.0-4.2 (m,4H), 4.75 (m, 1H), 6.52 (s, 1H), 6.85 (s, 1H), 7.35 (m, 2H), 7.65 (s,1H), 8.6 (s, 1H), 8.7 (d, 1H), 10.3 (s, 1H); Mass Spectrum: M+H⁺ 522 and524.

EXAMPLE 294-(2,4-dichloro-5-methoxyanilino)-7-(3-piperazin-1-ylpropoxy)-5-tetrahydropyran-4-yloxyquinazolinedihydrochloride

[1020] A mixture of4-(2,4-dichloro-5-methoxyanilino)-7-[3-(4-tert-butoxycarbonylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazoline(0.12 g) and trifluoroacetic acid (2 ml) was stirred at ambienttemperature for 2 hours. The mixture was evaporated and the residue wastriturated under diethyl ether. The resultant solid was isolated anddried under vacuum. The solid was dissolved in diethyl ether and 6Mhydrogen chloride gas in diethyl ether (0.5 ml) was added. The resultantsolid was isolated, washed with diethyl ether and dried under vacuum.There was thus obtained the title compound (0.112 g); NMR Spectrum:(DMSOd₆ and CF₃CO₂H) 1.9-2.1 (m, 2H), 2.15 (d, 2H), 2.28-2.4 (m, 2H),3.4 (m, 2H), 3.4-3.9 (m, 10H), 3.92 (s, 3H), 3.95 (m, 2H), 4.39 (t, 2H),5.2 (m, 1H), 7.0 (d, 1H), 7.2 (d, 1H), 7.78 (s, 1H), 7.82 (s, 1H), 8.9(s, 1H); Mass Spectrum: M+H⁺ 562 and 564.

[1021] The4-(2,4-dichloro-5-methoxyanilino)-7-[3-(4-tert-butoxycarbonylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazolineused as a starting material was prepared as follows:

[1022] Using an analogous procedure to that described in Example 12,4-(2,4-dichloro-5-methoxyanilino)-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline(0.109 g) was reacted with1-tert-butoxycarbonyl-4-(3-hydroxypropyl)piperazine (0.074 g) to give4-(2,4-dichloro-5-methoxyanilino)-7-[3-(4-tert-butoxycarbonylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazoline(0.12 g).

Example +4-(2,4-dichloro-5-methoxyanilino)-7-piperidin-4-ylmethoxy-5-tetrahydropyran-4-yloxyquinazoline

[1023] A mixture of4-(2,4-dichloro-5-methoxyanilino)-7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)-5-tetrahydropyran-4-yloxyquinazoline(0.11 g) and trifluoroacetic acid (2 ml) was stirred at ambienttemperature for 2 hours. The mixture was evaporated and the residue wastriturated under diethyl ether. The resultant solid was isolated anddried under vacuum. The solid was dissolved in diethyl ether and 6Mhydrogen chloride gas in diethyl ether (0.5 ml) was added. The resultantsolid was isolated, washed with diethyl ether and dried under vacuum.There was thus obtained the dihydrochloride salt of the title compound.The solid was dissolved in methylene chloride and few drops of asaturated methanolic ammonia solution was added. The solution was pouredonto a chromatography column filled with silica and eluted with a 24:1mixture of methylene chloride and a saturated methanolic ammoniasolution. There was thus obtained the title compound (0.08 g); NMRSpectrum: (CDCl₃) 1.9-2.1 (m, 2H), 1.95 (d, 2H), 1.9-2.15 (m, 3H), 2.52(d, 2H), 2.7 (m, 2H), 3.2 (d, 2H), 3.6 (m, 2H), 3.9-4.0 (m, 2H), 4.05(s, 3H), 4.1 (td, 2H), 4.75 (m, 1H), 6.6 (d, 1H), 6.85 (m, 1H), 7.45 (s,1H), 8.4 (s, 1H), 8.6 (s, 1H); Mass Spectrum: M+H⁺ 533 and 535.

[1024] The4-(2,4-dichloro-5-methoxyanilino)-7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)-5-tetrahydropyran-4-yloxyquinazolineused as a starting material was prepared as follows:

[1025] Using an analogous procedure to that described in Example 12,4-(2,4-dichloro-5-methoxyanilino)-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline(0.109 g) was reacted with 1-tert-butoxycarbonylpiperidin-4-ylmethanol(0.065 g) to give4-(2,4-dichloro-5-methoxyanilino)-7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)-5-tetrahydropyran-4-yloxyquinazoline(0.11 g).

EXAMPLE 314-(6-chloro-2,3-methylenedioxyanilino)-7-fluoro-5-piperidin-4-yloxyquinazolinedihydrochloride

[1026] A mixture of5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(6-chloro-2,3-methylenedioxyanilino)-7-fluoroquinazolinedihydrochloride (0.12 g) and a 2M solution of hydrogen chloride indiethyl ether (5 ml) was stirred at ambient temperature for 1 hour. Theresultant precipitate was isolated, washed with diethyl ether and driedunder vacuum. There was thus obtained the title compound (0.086 g); NMRSpectrum: (DMSOd₆) 2.1-2.3 (m, 4H), 3.0-3.15 (m, 2H), 3.3 (m, 2H), 5.1(m, 1H), 6.12 (s, 2H), 7.01 (d, 1H), 7.1 (d, 1H), 7.3 (d, 1H), 7.53 (d,1H), 8.75 (s, 1H), 9.05 (br s, 1H), 9.3 (br s, 1H), 9.95 (br s, 1H);Mass Spectrum: M+H⁺ 417 and 419.

[1027] The5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(6-chloro-2,3-methylenedioxyanilino)-7-fluoroquinazolinedihydrochloride used as a starting material was prepared as follows:

[1028] Sodium hydride (60% dispersion in mineral oil; 0.55 g) was addedportionwise to a solution of tert-butyl4-hydroxypiperidine-1-carboxylate (1.65 g) in DMF (10 ml) and theresultant mixture was stirred at ambient temperature for 15 minutes.5,7-Difluoro-3,4-dihydroquinazolin-4-one (1 g) was added and the mixturewas stirred at ambient temperature for 30 minutes. The mixture waspoured into water (100 ml) and, with vigorous stirring, glacial aceticacid was added to acidify the mixture to pH5. The resultant solid wasisolated, washed with water and with diethyl ether and dried undervacuum. There was thus obtained5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-7-fluoro-3,4-dihydroquinazolin-4-one(1.4 g); NMR Spectrum: (CDCl₃) 1.47 (s, 9H), 1.94 (m, 4H), 3.5-3.8 (m,4H), 4.7 (m, 1H), 6.68 (m, 1H), 7.0 (m, 1H), 7.9 (s, 1H), 10.55 (br s,1H); Mass Spectrum: M+H⁺ 364.

[1029] A mixture of5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-7-fluoro-3,4-dihydroquinazolin-4-one(0.15 g), triphenylphosphine (0.216 g), carbon tetrachloride (0.12 ml)and 1,2-dichloroethane (5 ml) was stirred and heated to 70° C. for 1hour. The mixture was evaporated and the residue was purified by columnchromatography on silica using a 9:1 mixture of methylene chloride andethyl acetate as eluent. There was thus obtained5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-chloro-7-fluoroquinazoline(0.1 g); NMR Spectrum: (CDCl₃) 1.48 (s, 9H), 2.0 (m, 4H), 3.5-3.7 (m,4H), 4.8 (m, 1H), 6.8 (m, 1H), 7.3 (m, 1H), 8.9 (s, 1H); Mass Spectrum:M+H⁺ 382 and 384.

[1030] A mixture of the material so obtained,6-chloro-2,3-methylenedioxyaniline (0.049 g), 5M hydrogen chloride inisopropanol (1 drop) and isopropanol (1 ml) was stirred and heated to50° C. for 15 minutes and then to 80° C. for 45 minutes. The precipitatewas isolated, washed in turn with isopropanol, ethyl acetate and diethylether and dried under vacuum. There was thus obtained5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(6-chloro-2,3-methylenedioxyanilino)-7-fluoroquinazolinedihydrochloride (0.065 g); NMR Spectrum: (DMSOd₆) 1.4 (s, 9H), 1.8-2.0(m, 2H), 2.0-2.15 (m, 2H), 3.05 (br s, 2H), 3.9 (d, 2H), 5.05 (m, 1H),6.11 (s, 2H), 7.1 (d, 1H), 7.16 (d, 1H), 7.2 (m, 1H), 7.52 (d, 1H), 8.7(s, 1H), 9.92 (br s, 1H); Mass Spectrum: M+H⁺ 517 and 519.

EXAMPLE 324-(6-chloro-2,3-methylenedioxyanilino)-5-piperidin-4-yloxyquinazolinedihydrochloride

[1031] Using an analogous procedure to that described in Example 31,5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(6-chloro-2.3-methylenedioxyanilino)quinazolinedihydrochloride (0.14 g) was reacted with hydrogen chloride to give thetitle compound (0.113 g); NMR Spectrum: (DMSOd₆) 2.15-2.34 (m, 4H), 3.15(m, 2H), 3.3 (m, 2H), 5.17 (m, 1H), 6.17 (s, 2H), 7.07 (d, 1H), 7.16 (d,1H), 7.58 (m, 1H), 8.06 (m, 1H), 8.88 (s, 1H), 9.14 (br s, 1H), 9.32 (brs, 1H), 10.28 (s, 1H); Mass Spectrum: M+H⁺ 399 and 401.

[1032] The5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(6-chloro-2,3-methylenedioxyanilino)quinazolinedihydrochloride used as a starting material was prepared as followsusing analogous procedures to those described in the portion of example31 that is concerned with the preparation of starting materials:

[1033] Thus, tert-butyl 4-hydroxypiperidine-1-carboxylate (0.33 g) wasreacted with 5-fluoro-3,4-dihydroquinazolin-4-one (0.18 g) to give5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-3,4-dihydroquinazolin-4-one(0.39 g); NM Spectrum: (CDCl₃) 1.5 (s, 9H), 1.9-2.0 (m, 4H), 3.52 (m,2H), 3.7 (m, 2H), 4.72 (m, 1H), 6.95 (d, 1H), 7.32 (d, 1H), 7.65 (m,1H), 7.95 (s, 1H), 10.22 (br s, 1H); Mass Spectrum: M+H⁺ 346;

[1034]5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-3,4-dihydroquinazolin-4-one(0.31 g) was reacted with triphenylphosphine and carbon tetrachloride togive 5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-chloroquinazoline(0.156 g); NM Spectrum: (CDCl₃) 1.5 (s, 9H), 1.9-2.1 (m, 4H), 3.5-3.8(m, 4H), 4.8 (m, 1H), 7.05 (d, 1H), 7.65 (d, 1H), 7.82 (m, 1H), 8.95 (s,1H); Mass Spectrum: M+H⁺ 364 and 366; and

[1035] a portion (0.124 g) of the material so obtained and6-chloro-2,3-methylenedioxyaniline (0.064 g) were reacted to give5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(6-chloro-2,3-methylenedioxyanilino)quinazolinedihydrochloride (0.14 g); NMR Spectrum: (DMSOd₆) 1.4 (s, 9H), 1.85-2.0(m, 2H), 2.1 (m, 2H), 2.95-3.2 (m, 2H), 3.92 (d, 2H), 5.1 (m, 1H), 6.15(s, 2H), 7.08 (d, 1H), 7.15 (d, 1H), 7.55 (d, 1H), 7.6 (d, 1H), 8.05 (m,1H), 8.86 (s, 1H), 10.35 (s, 1H); Mass Spectrum: M+H⁺ 499 and 501.

EXAMPLE 334-(6-chloro-2,3-methylenedioxyanilino)-7-methoxy-5-piperidin-4-yloxyquinazoline

[1036] A mixture of5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(6-chloro-2,3-methylenedioxyanilino)-7-methoxyquinazolinedihydrochloride (2.39 g), trifluoroacetic acid (10 ml) and methylenechloride (35 ml) was stirred at ambient temperature for 1.5 hours. Themixture was evaporated and the residue was partitioned between ethylacetate and a 1N aqueous sodium hydroxide solution. The organic layerwas washed with water and brine, dried over magnesium sulphate andevaporated. The residue was purified by column chromatography on silicausing a 19:1 mixture of methylene chloride and methanol as eluent. Therewas thus obtained the title compound (1.44 g); NMR Spectrum: (CDCl₃)1.8-2.0 (m, 2H), 2.15-2.3 (m, 2H), 2.75-2.9 (m, 2H), 3.1-3.2 (m, 2H),3.9 (s, 3H), 4.65 (m, 1H), 6.0 (s, 2H), 6.46 (d, 1H), 6.72 (d, 1H), 6.8(d, 1H), 6.91 (d, 1H), 8.5 (s, 1H), 9.21 (s, 1H); Mass Spectrum: M+H⁺429 and 431.

[1037] The5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(6-chloro-2,3-methylenedioxyanilino)-7-methoxyquinazolinedihydrochloride used as a starting material was prepared as follows:

[1038] Di-tert-butyl azodicarboxylate (1.13 g) was added portionwise toa stirred mixture of5-hydroxy-7-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (1g), tert-butyl 4-hydroxypiperidine-1-carboxylate (0.788 g),triphenylphosphine (1.28 g) and metlhylene chloride (15 ml) which hadbeen cooled to 10° C. The mixture was allowed to warm to ambienttemperature and was stirred for 1 hour. The mixture was evaporated andthe residue was dissolved in methanol (25 ml). Sodium hydroxide (0.2 g)was added and the mixture was stirred at ambient temperature for 1 hour.The resultant mixture was evaporated and the residue was purified bycolumn chromatography on silica using a 47:50:3 mixture of methylenechloride, ethyl acetate and methanol as eluent. There was thus obtained5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-7-methoxy-3,4-dihydroquinazolin-4-one(1.09 g); NMR Spectrum: (CDCl₃) 1.5 (s, 9H), 1.87-2.0 (m, 4H), 3.48-3.6(m, 2H), 3.6-3.75 (m, 2H), 3.9 (s, 3H), 4.65 (m, 1H), 6.5 (d, 1H), 6.77(d, 1H), 7.91 (s, 1H), 10.7 (br s, 1H); Mass Spectrum: M+H⁺ 376.

[1039] Using an analogous procedure to that described in the portion ofExample 31 that is concerned with the preparation of starting materials,5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-7-methoxy-3,4-dihydroquinazolin-4-one(1 g) was reacted with triphenylphosphine and carbon tetrachloride togive5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-chloro-7-methoxyquinazoline(0.8 g); NMR Spectrum: (CDCl₃) 1.5 (s, 9H), 1.9-2.1 (m, 4H), 3.5-3.7 (m,4H), 3.96 (s, 3H), 4.72 (m, 2H), 6.6 (d, 1H), 6.98 (d, 1H), 8.82 (s,1H); Mass Spectrum: M+H⁺ 394 and 396.

[1040] Using an analogous procedure to that also described in theportion of Example 31 that is concerned with the preparation of startingmaterials,5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-chloro-7-methoxyquinazoline(0.14 g) and 6-chloro-2,3-methylenedioxyaniline (0.064 g) were reactedto give5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(6-chloro-2,3-methylenedioxyanilino)-7-methoxyquinazolinedihydrochloride (0.17 g); NMR Spectrum: (DMSOd₆) 1.42 (s, 9H), 1.8-2.0(m, 2H), 2.0-2.15 (m, 2H), 3.0-3.2 (m, 2H), 3.85-3.95 (m, 2H), 3.99 (s,3H), 5.1 (m, 1H), 6.96 (d, 1H), 7.05 (d, 1H), 7.12 (s, 1H), 7.15 (d,1H), 8.78 (s, 1H), 10.1 (s, 1H); Mass Spectrum: M+H⁺ 529 and 531.

EXAMPLE 344-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-piperidin-4-yloxyquinazoline

[1041] A mixture of7-benzyloxy-5-[N-(tert-butoxycarbonyl)piperidin-4-yloxy]-4-(6-chloro-2,3-methylenedioxyanilino)quinazolinedihydrochloride (2.3 g) and trifluoroacetic acid 28 ml) was stirred andheated to 80° C. for 6 hours. The mixture was evaporated and the residuewas dissolved in water and the solution was basified to pH10 by theaddition of 1N aqueous sodium hydroxide solution. The mixture wasstirred at ambient temperature for 1 hour. The solid was isolated,washed with water and dried under vacuum. There was thus obtained thetitle compound (1.1 g); NMR Spectrum: (DMSOd₆) 1.6-1.8 (m, 2H), 2.0-2.15(m, 2H), 2.65-2.75 (m, 2H), 2.9-3.05 (m, 2H), 4.8 (m, 1H), 6.1 (s, 2H),6.62 (s, 1H), 6.7 (s, 1H), 6.92 (d, 1H), 7.05 (d, 1H), 8.25 (s, 1H), 9.2(s, 1H); Mass Spectrum: M+H⁺ 415 and 417.

EXAMPLE 355-[N-(tert-butoxycarbonyl)piperidin-4-yloxy]-4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxyquinazoline

[1042] A mixture of4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-piperidin-4-yloxyquinazoline(1.4 g), di-tert-butyl dicarbonate (0.737 g) and DMF (14 ml) was stirredat ambient temperature for 2 hours. The mixture was evaporated and theresidue was partitioned between ethyl acetate and water. The organicphase was washed with brine, dried over magnesium sulphate andevaporated. The residue was purified by column chromatography on silicausing a 24:1 mixture of methylene chloride and methanol as eluent. Therewas thus obtained the title compound (1.2 g); NMR Spectrum: (CDCl₃) 1.5(s, 9H), 1.7-1.9 (m, 2H), 2.0-2.15 (m, 2H), 3.0-3.15 (m, 2H), 3.8-3.95(m, 2H), 4.6 (m, 1H), 6.02 (s, 2H), 6.55 (s, 1H), 6,72 (d, 1H), 6.98 (m,2H), 8.4 (s, 1H), 9.4 (s, 1H); Mass Spectrum: M+H⁺ 515 and 517.

EXAMPLE 364-(6-chloro-2,3-methylenedioxyanilino)-5-piperidin-4-yloxy-7-(2,2,2-trifluoroethoxy)quinazoline

[1043] A mixture of5-[N-(tert-butoxycarbonyl)piperidin-4-yloxy]-4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxyquinazoline(0.15 g), 2,2,2-trifluoroethyl 4-toluenesulphonate (0.089 g), potassiumcarbonate (0.1 g) and DMF (3 ml) was stirred and heated to 95° C. for 24hours. The mixture was cooled to ambient temperature and partitionedbetween ethyl acetate and water. The organic solution was washed with 1Naqueous sodium hydroxide solution and with brine and dried overmagnesium sulphate. The organic solution was filtered and a 6N solutionof hydrogen chloride in diethyl ether (2 ml) was added. The mixture wasstirred at ambient temperature for 16 hours. The mixture was evaporated.The residue was dissolved in methylene chloride (3 ml) and a saturatedmethanolic ammonia solution (1 ml) was added. The mixture was filteredand the filtrate was evaporated. The residue was purified by columnchromatography on silica using a 19:1 mixture of methylene chloride anda saturated methanolic ammonia solution as eluent. There was thusobtained the title compound (0.061 g); NMR Spectrum: (CDCl₃) 1.85-2.0(m, 2H), 2.3 (m, 2H), 2.8-2.95 (m, 2H), 3.1-3.3 (m, 2H), 4.5 (m, 2H),4.72 (m, 1H), 6.08 (s, 2H), 6.6 (d, 1H), 6.75 (d, 1H), 6.82 (d, 1H), 7.0(d, 1H), 8.58 (s, 1H), 9.32 (s, 1H); Mass Spectrum: M+H⁺ 497 and 499.

EXAMPLE 374-(6-chloro-2,3-methylenedioxyanlino)-5-(N-methylpiperidin-4-yloxy)quinazoline

[1044] 4-Hydroxy-1-methylpiperidine (0.049 g) was added to a stirredsuspension of sodium hydride (60% dispersion in mineral oil, 0.043 g) inDMF (2 ml) and the mixture was stirred at ambient temperature for 5minutes. The dihydrochloride salt of4-(6-chloro-2,3-methylenedioxyanilino)-5-fluoroquinazoline was treatedwith a saturated methanolic ammonia solution to give the free base (0.1g) which was added to the above-mentioned solution of the sodium salt of4-hydroxy-1-methylpiperidine. The resultant mixture was stirred andheated to 50° C. for 30 minutes. The mixture was cooled to ambienttemperature and partitioned between ethyl acetate and water. The organiclayer was washed with water and with brine, dried over magnesiumsulphate and evaporated. The residue was purified by columnchromatography on silica using a 25:24:1 mixture of ethyl acetate,methylene chloride and a saturated methanolic ammonia solution aseluent. There was thus obtained4-(6-chloro-2,3-methylenedioxyanilino)-5-(N-methylpiperidin-4-yloxy)quinazoline(0.054 D); NMR Spectrum: (CDCl₃) 1.95-2.1 (m, 2H), 2.1-2.25 (m, 2H), 2.3(s, 3H), 2.3-2.4 (m, 2H), 2.7 (br s, 2H), 4.65 (m, 1H), 6.01 (s, 2H),6.7 (d, 1H), 6.8 (d, 1H), 6.85 (d, 1H), 7.45 (d, 1H), 7.6 (m, 1H), 8.56(s, 1H), 9.5 (br s, 1H); Mass Spectrum: M+H⁺ 413 and 415.

[1045] The 4-(6-chloro-2,3-methylenedioxyanilino)-5-fluoroquinazolinedihydrochloride used as a starting material was prepared was prepared asfollows using analogous procedures to those described in the portion ofExample 31 that is concerned with the preparation of starting materials:

[1046] Thus, 5-fluoro-3,4-dihydroquinazolin-4-one (2 g) was reacted withtriphenylphosphine and carbon tetrachloride to give5-fluoro-4-chloroquinazoline (1.34 g); NMR Spectrum: (CDCl₃) 7.4-7.5 (m,1H), 7.9-8.0 (m, 2H), 9.1 (s, 1H); and

[1047] a portion (0.4 g) of the material so obtained and6-chloro-2,3-methylenedioxyaniline (0.413 g) were reacted to give4-(6-chloro-2,3-methylenedioxyanilino)-5-fluoroquinazolinedihydrochloride (0.73 g); NMR Spectrum: (DMSOd₆) 6.18 (s, 2H), 7.05 (d,1H), 7.12 (d, 1H), 7.7 (m, 1H), 7.85 (d, 1H), 8.12 (m, 1H), 8.87 (s,1H); Mass Spectrum: M+H⁺ 318 and 320.

EXAMPLE 384-(6-chloro-2,3-methylenedioxyanilino)-7-isopropoxy-5-(N-methylpiperidin-4-yloxy)quinazoline

[1048] Sodium triacetoxyborohydride (0.087 g) was added portionwise to astirred mixture of4-(6-chloro-2,3-methylenedioxyanilino)-7-isopropoxy-5-piperidin-4-yloxyquinazohne(0.125 g), aqueous formaldehyde (13N, 0.042 ml), acetic acid (0.019 ml),methylene chloride (5 ml) and methanol (2 ml) and the resultant mixturewas heated to reflux for 3 minutes. The mixture was evaporated and theresidue was partitioned between ethyl acetate and 1N aqueous sodiumhydroxide solution. The organic layer was washed with brine, dried overmagnesium sulphate and evaporated to give the title compound (0.11 g);NMR Spectrum: (CDCl₃) 1.42 (d, 6H), 1.95-2.1 (m, 2H), 2.15-2.25 (m, 2H),2.3 (s, 3H), 2.3-2.4 (m, 2H), 2.7-2.8 (m, 2H), 4.6 (m, 1H), 4.72 (m,1H), 6.05 (s, 2H), 6.5 (d, 1H), 6.75 (d, 1H), 6.82 (d, 1H), 6.99 (d,1H), 8.52 (s, 1H), 9.3 (s, 1H); Mass Spectrum: M+H⁺ 471 and 473.

EXAMPLE 394-(6-chloro-2,3-methylenedioxyanilino)-5-piperidin-4-ylmethoxyquinazolinedihydrochloride

[1049] Using an analogous procedure to that described in Example 37,N-(tert-butoxycarbonyl)piperidin-4-ylmethanol was reacted with4-(6-chloro-2,3-methylenedioxyanilino)-5-fluoroquinazoline (0.1 g). Theproduct so obtained was dissolved in a 2M solution of hydrogen chloridein diethyl ether (20 ml) and stirred at ambient temperature for 3 hours.The mixture was evaporated and the residue was triturated under diethylether. The solid so obtained was washed with diethyl ether and driedunder vacuum. There was thus obtained the tilte compound (0.121 g); NMRSpectrum: (DMSOd₆) 1.5-1.6 (m, 2H), 1.9-2.0 (m, 2H), 2.3-2.4 (m, 1H),2.8-2.9 (m, 2H), 3.3 (d, 2H), 4.42 (d, 2H), 6.15 (s, 2H), 7.07 (d, 1H),7.15 (d, 1H), 7.53 (m, 2H), 8.06 (m, 1H), 8.87 (s, 1H), 10.57 (br s,1H); Mass Spectrum: M+H⁺ 413 and 415.

EXAMPLE 404-(6-chloro-2,3-methylenedioxyanilino)-5-(L-methylpiperidin-4-ylmethoxy)quinazolinedihydrochloride

[1050] Using an analogous procedure to that described in Example 38,4-(6-chloro-2,3-methylenedioxyanilino)-5-piperidin-4-ylmethoxyquinazoline(obtained from the dihydrochloride salt by trituration under a saturatedmethanolic ammonia solution) was reacted with aqueous formaldehyde andsodium triacetoxyborohydride. The reaction product, obtained as the freebase, was triturated under a 2M solution of hydrogen chloride in diethylether. The resultant precipitate was isolated, washed with diethyl etherand dried under vacuum. There was thus obtained the title compound, aportion of which was converted to the free base by trituration under asaturated methanolic ammonia solution. The free base gave the followingdata: NMR Spectrum: (CDCl₃) 1.35-1.55 (m, 2H), 1.9-2.1 (m, 5H), 2.3 (s,3H), 2.9 (d, 2H), 4.12 (d, 2H), 6.04 (s, 2H), 6.75 (d, 1H), 6.9 (d, 1H),6.98 (d, 1H), 7.48 (d, 1H), 7.64 (m, 1H), 8.62 (s, 1H), 9.38 (s, 1H);Mass Spectrum: M+H⁺ 427 and 429.

EXAMPLE 414-(6-chloro-2,3-methylenedioxyanilino)-7-(3-piperidinopropoxy)-5-tetrahydropyran-4-yloxyquinazoline

[1051] A mixture of7-(3-bromopropoxy)-4-(6-chloro-2,3-methylenedioxyanilino)-5-tetrahydropyran-4-yloxyquinazoline(0.536 g), piperidine (0.12 ml), potassium carbonate (0.4 g) and DMF (2ml) was stirred at ambient temperature for 16 hours. The mixture wasevaporated and the residue was triturated under methylene chloride. Themixture was filtered and the filtrate was purified by columnchromatography on silica using initially a 1:1 mixture of ethyl acetateand methylene chloride and then a 10:9:1 mixture of ethyl acetate,methylene chloride and a saturated methanolic ammonia solution aseluent. There was thus obtained the title compound (0.53 g); NMRSpectrum: (CDCl₃) 1.4-1.5 (m, 2H), 1.55-1.7 (m, 4H), 1.9-2.1 (m, 4H),2.2-2.3 (m, 2H), 2.4 (m, 4H), 2.5 (m, 2H), 3.6-3.7 (m, 2H), 4.0-4.1 (m,2H), 4.15 (m, 2H), 4.8 (m, 1H), 6.08 (s, 2H), 6.52 (d, 1H), 6.75 (d,1H), 6.85 (d, 1H), 7.0 (d, 1H), 8.55 (s, 1H), 9.35 (s, 1H); MassSpectrum: M+H⁺ 541 and 543.

[1052] The7-(3-bromopropoxy)-4-(6-chloro-2,3-methylenedioxyanilino)-5-tetrahydropyran-4-yloxyquinazolineused as a starting material was prepared as follows:

[1053] Di-tert-butyl azodicarboxylate (1.66 g) was added to a stirredmixture of4(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline(1.5 g), 3-bromopropan-1-ol (0.49 ml), triphenylphosphine (1.9 g) andmethylene chloride (20 ml) and the mixture was stirred at ambienttemperature for 1 hour. A second portion (1.66 g) of di-tert-butylazodicarboxylate was added and the mixture was stirred at ambienttemperature for 16 hours. The mixture was filtered and the filtrate waspurified by column chromatography on silica using initially a 1:1mixture of ethyl acetate and methylene chloride and then a 25:24:1mixture of ethyl acetate, methylene chloride and methanol as eluent. Thematerial so obtained was triturated under diethyl ether. The resultantsolid was isolated, washed with diethyl ether and dried under vacuum togive the required starting material (0.536 g).

EXAMPLE 42

[1054] Using an analogous procedure to that described in Example 41, theappropriate haloalkoxy substituted quinazoline was reacted with theappropriate amine to give the compound described in Table VII. TABLE VII

No. & Note (R¹)_(m) Q¹ (R²)_(n) [1] 7-[3-(4-hydroxypiperidin-4-tetrahydropyranyl 6-chloro-2,3-methylenedioxy 1-yl)propoxy]

[1055] Note

[1056] [1] 4-Hydroxypiperidine was used as the amine. The product gavethe following data: NMR Spectrum: (CDCl₃) 1.5-1.7 (m, 2H), 1.85-2.05 (m,6H), 2.05-2.25 (m, 4H), 2.5 (m, 2H), 2.8 (m, 2H), 3.55-3.65 (m, 2H), 3.6(m, 1H), 3.95-4.05 (m, 2H), 4.12 (m, 2H), 4.75 (m, 1H), 6.05 (s, 2H),6.5 (s, 1H), 6.7 (d, 1H), 6.8 (d, 1H), 6.95 (d, 1H), 8.5 (s, 1H), 9.25(s, 1H); Mass Spectrum: M+H⁺ 557 and 559.

EXAMPLE 434-(6-chloro-2,3-methylenedioxyanilino)-7-piperidin-4-ylmethoxy-5-tetrahydropyran-4-yloxyquinazoline

[1057] A mixture of7-[N-(tert-butoxycarbonyl)piperidin-4-ylmethoxy]-4-(6-chloro-2,3-methylenedioxyanilino)-5-tetrahydropyran-4-yloxyquinazoline(0.25 g), trifluoroacetic acid (1 ml) and methylene chloride (1 ml) wasstirred at ambient temperature for 1.5 hours. The mixture was evaporatedand the residue was purified by column chromatography on silica using a93:7 mixture of methylene chloride and a saturated methanolic ammoniasolution as eluent. The material so obtained was partitioned betweenethyl acetate and an aqueous ammonium hydroxide solution. The organiclayer was dried over magnesium sulphate and evaporated. There was thusobtained the title compound (0.07 g); NMR Spectrum: (CDCl₃ and D₂O)1.5-1.7 (m, 2H), 1.9-2.1 (m, 4H), 2.2-2.3 (m, 2H), 2.8 (m, 2H), 3.32 (d,2H), 3.65 (m, 2H), 3.9-4.1 (m, 3H), 4.8 (m, 1H), 6.08 (s, 2H), 6.52 (brs, 1H), 6.72 (d, 1H), 6.8 (s, 1H), 6.98 (d, 1H), 8.5 (s, 1H); MassSpectrum: M+H⁺ 513 and 515.

EXAMPLE 444-(6-chloro-2,3-methylenedioxyanilino)-7-(N-methylpiperidin-4-ylmethoxy)-5-tetrahydropyran-4-yloxyquinazoline

[1058] A mixture of7-[N-(tert-butoxycarbonyl)piperidin-4-ylmethoxy]-4-(6-chloro-2,3-methylenedioxyanilino)-5-tetrahydropyran-4-yloxyquinazoline(0.25 g), a concentrated aqueous formaldehyde solution (37%, 0.5 ml) andformic acid (5 al) was stirred and heated to 100° C. for 2 hours. Themixture was cooled to ambient temperature and evaporated. The residuewas purified by column chromatography on silica using a 24:1 mixture ofmethylene chloride and a saturated methanolic ammonia solution aseluent. The material so obtained was partitioned between methylenechloride and an aqueous ammonium hydroxide solution. The organic layerwas dried over magnesium sulphate and evaporated. There was thusobtained the title compound (0.1 g); NMR Spectrum: (CDCl₃) 1.4-1.6 (m,2H), 1.75-1.9 (m, 3H), 1.9-2.1 (m, 4H), 2.2-2.3 (m, 2H), 2.29 (s, 3H),2.9 (d, 2H), 3.6-3.7 (m, 2H), 3.95 (d, 2H), 4.0-4.1 (m, 2H), 4.75 (m,1H), 6.05 (s, 2H), 6.5 (d, 1H), 6.72 (d, 1H ), 6.81 (d, 1H), 6.97 (d,1H), 8.5 (s, 1H), 9.26 (s, 1H); Mass Spectrum: M+H⁺ 527 and 529.

EXAMPLE 454-(6-chloro-2,3-methylenedioxyanilino)-7-[(2R)-2,3-epoxypropoxy]-5-tetrahydropyran-4-yloxyquinazoline

[1059] Caesium fluoride (0.46 g) and (2R)-(−)-glycidyl tosylate (0.275g) were added in turn to a solution of4-(6-chloro-2,3-methylenedioxyanilino)-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline(0.416 g) in DMF (5 ml) and the reaction mixture was stirred and heatedto 60° C. for 2 hours and to 70° C. for a further 1.5 hours. The mixturewas evaporated and the residue was partitioned between ethyl acetate anda saturated aqueous sodium bicarbonate solution. The organic layer waswashed with water and with brine, dried over magnesium sulphate andevaporated. The residue was purified by column chromatography on silicausing a 49:1 mixture of methylene chloride and methanol as eluent. Therewas thus obtained the title compound (0.36 g); NMR Spectrum: (CDCl₃)1.9-2.1 (m, 2H), 2.2-2.3 (m, 2H), 2.8 (m, 1H), 2.98 (m, 1H), 3.42 (m,1H), 3.6-3.7 (m, 2H), 3.95-4.1 (m, 3H), 4.45 (m, 1H), 4.8 (m, 1H), 6.02(s, 2H), 6.59 (m, 12H), 6.72 (d, 1H), 6.81 (d, 1H), 6.97 (d, 1H), 8.5(s, 1H), 9.27 (s, 1H); Mass Spectrum: M+H⁺ 472 and 474.

EXAMPLE 464-(6-chloro-2,3-methylenedioxyanilino)-7-[3-(4-cyanomethylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazoline

[1060] A mixture of4-(6-chloro-2,3-methylenedioxyanilino)-7-(3-piperazin-1-ylpropoxy)-5-tetrahydropyran-4-yloxyquinazoline(1.3 g), 2-chloroacetonitrile (0.167 ml), sodium iodide (0.036 g),potassium carbonate (0.331 g) and DMF (15 ml) was stirred at ambienttemperature for 5 hours. The mixture was evaporated and the residue waspartitioned between ethyl acetate and water. The organic phase waswashed with brine, dried over magnesium sulphate and evaporated. Theresidue was purified by column chromatography on silica using a 10:9:1mixture of ethyl acetate, methylene chloride and methanol as eluent.There was thus obtained the title compound (0.69 g); NMR Spectrum:(CDCl₃) 1.85-2.0 (m, 4H), 2.1 (m, 2H), 2.4-2.5 (m, 6H), 2.5-2.6 (m, 4H),3.42 (s, 2H), 3.5-3.6 (m, 2H), 3.9-4.0 (m, 2H), 4.0-4.1 (m, 2H), 4.7 (m,1H), 6.0 (s, 2H), 6.42 (s, 1H), 6.65 (d, 1H), 6.78 (d, 1H), 6.9 (d, 1H),8.42 (s, 1H), 9.2 (s, 1H ); Mass Spectrum: M+H⁺ 581 and 583.

EXAMPLE 474-(6-chlorobenzofuran-7-ylamino)-7-(2-pyrrolidin-1-ylethoxy)-5-cyclopentyloxyquinazolinedihydrochloride

[1061] Sodium hexamethyldisilazane (1M solution in THF; 0.55 ml) wasadded to a solution of 7-amino-6-chlorobenzofuran (0.093 g) in DMF (3ml) which was cooled to 10° C. and the mixture was stirred at 10° C. for5 minutes. A solution of4-chloro-5-cyclopentyloxy-7-(2-pyrrolidin-1-ylethoxy)quinazoline (0.1 g)in DMF (8 ml) was added and the mixture was stirred at ambienttemperature for 1 hour. The mixture was partitioned between ethylacetate and water. The organic layer was evaporated and the residue waspurified by column chromatography on silica using a 49:1 mixture ofmethylene chloride and methanol as eluent. The material so obtained wasdissolved in diethyl ether and 6M hydrogen chloride in isopropanol (0.1ml) was added. The mixture was stirred for 5 minutes and thenevaporated. There was thus obtained the title compound as adihydrochloride salt (0.095 g), a portion of which was converted intothe free base using an analogous procedure to that described in Example3. The free base gave the following characterising data: NMR Spectrum:(CDCl₃) 1.55-1.75 (m, 4H), 1.75-1.95 (m, 4H), 2.08 (m, 2H), 2.6-2.75 (m,4H), 3.0 (m, 2H), 4.25 (m, 2H), 5.05 (m, 1H), 6.6 (d, 1H), 6.8 (d, 1H),6.85 (d, 1H), 7.38 (d, 1H), 7.45 (d, 1H), 7.6 (d, 1H), 8.42 (s, 1H), 9.5(s, 1H); Mass Spectrum: M+H⁺ 493 and 495.

[1062] The 7-amino-6-chlorobenzofuran used as a starting material wasprepared as follows: Sodium hydride (60% dispersion in mineral oil; 4.6g) was added to a stirred solution of 6-chloroanthranilic acid (18 g) inDMF (100 ml) and the mixture was stirred at ambient temperature for 30minutes. Ethyl iodide (10 ml) was added and the reaction mixture wasstirred at ambient temperature for 2 days. The solvent was evaporatedand the residue was partitioned between ethyl acetate and water. Theorganic phase was washed in turn with water and brine, dried overmagnesium sulphate and evaporated. The residue was purified by columnchromatography on silica using a 4:1 mixture of petroleum ether (b.p.60-80° C.) and ethyl acetate as eluent. There was thus obtained ethyl6-chloroanthranilate (15.8 g) as an oil; NMR Spectrum: (DMSOd₆) 1.3 (t,3H), 4.3 (q, 2H), 5.7 (br s, 2H), 6.6 (d, 1H), 6.7 (d, 1H), 7.1 (t, 1H).

[1063] A solution of sodium nitrite (4.5 g) in water (100 ml) was addeddropwise during 5 minutes to a stirred suspension of ethyl6-chloroanthranilate (12.7 g) in a mixture of concentrated sulphuricacid (27.9 ml), water (38 ml) and ice (76 g). The reaction mixture wasstirred at 0°C. for an additional 20 minutes and then heated to 120° C.for 1 hour. The resultant mixture was poured into a mixture of ice andwater and the product was extracted with diethyl ether. The organicphase was washed in turn with water and brine, dried over magnesiumsulphate and evaporated. The residue was purified by columnchromatography on silica using a 4:1 mixture of petroleum ether (b.p.60-80° C.) and methylene chloride as eluent. There was thus obtainedethyl 6-chloro-2-hydroxybenzoate (9.8 g); NMR Spectrum: (DMSOd₆) 1.3 (t,3H), 4.3 (q, 2H), 6.9 (d, 1H), 6.95 (d, 1H), 7.25 (d, 1H), 10.45 (br s,1H).

[1064] Allyl bromide (5.5 ml) was added to a stirred mixture of ethyl6-chloro-2-hydroxybenzoate (9.8 g), 1,5,7-triazabicyclo[4,4,0]dec-5-ene(10.4 g) and acetonitrile (250 ml) and the reaction mixture was stirredat ambient temperature for 20 hours. The mixture was evaporated and theresidue was purified by column chromatography on silica using a 17:3mixture of petroleum ether (b.p. 60-80° C.) and diethyl ether as eluent.There was thus obtained ethyl 2-allyloxy-6-chlorobenzoate (10.3 g); NMRSpectrum: (DMSOd₆) 1.3 (t, 3H), 4.35 (q, 2H), 4.65 (d, 2H), 5.25 (d,1H), 5.4 (d, 1H), 6.0 (m, 1H), 7.15 (m, 2H), 7.45 (t, 1H).

[1065] The material so obtained was heated to 230° C. for 1 hour. Thereaction product was cooled to ambient temperature and purified bycolumn chromatography on silica using a 4:1 mixture of petroleum ether(b.p. 60-80° C.) and methylene chloride as eluent. There was thusobtained ethyl 3-allyl-6-chloro-2-hydroxybenzoate (7.3 g); NMR Spectrum:(DMSOd₆) 1.3 (t, 3H), 3.3 (m, 2H), 4.35 (q, 2H), 5.05 (m, 2H), 5.95 (m,1H), 6.95 (d, 1H), 7.15 (d, 1H), 9.7 (br s, 1H).

[1066] The material so obtained was dissolved in methanol and cooled to−78° C. Ozone was bubbled through the solution for 30 min. Dimethylsulfide (5.4 ml) was added and the reaction mixture was allowed to warmto ambient temperature. The mixture was evaporated and the residue waspartitioned between diethyl ether and water. The organic phase waswashed in turn with water and brine, dried over magnesium sulphate andevaporated. The residue was purified by column chromatography on silicausing a 1:1 mixture of petroleum ether (b.p. 60-80° C.) and methylenechloride and then a 9:1 mixture of methylene chloride and diethyl etheras eluent. There was thus obtained2-(4-chloro-3-ethoxycarbonyl-2-hydroxyphenyl)acetaldehyde which wasimmediately suspended in 85% phosphoric acid (18 ml) and the mixture washeated to 100° C. for 1 hour. The mixture was cooled to ambienttemperature and partitioned between diethyl ether and water. The organicphase was washed in turn with water and brine, dried over magnesiumsulphate and evaporated. The residue was purified by columnchromatography on silica using a 1:1 mixture of petroleum ether (b.p.60-80° C.) and methylene chloride as eluent. There was thus obtainedethyl 6-chlorobenzofuran-7-carboxylate (5.9 g); NMR Spectrum: (DMSOd₆)1.35 (t, 3H), 4.45 (q, 2H), 7.10 (d, 1H), 7.45 (d, 1H), 7.85 (d, 1H),8.15 (d, 1H).

[1067] A mixture of the material so obtained, 35% aqueous potassiumhydroxide solution (12.7 ml) and methanol (20 ml) was stirred and heatedto reflux for 1 hour. The methanol was evaporated and the residue wasdiluted with water and acidified to pH1 by the addition of 6N aqueoushydrochloric acid. The resultant precipitate was isolated, washed withwater and dried under vacuum over phosphorus pentoxide to give6-chlorobenzofuran-7-carboxylic acid (4.6 g); NMR Spectrum: (DMSOd₆)7.05 (d, 1H), 7.4 (d, 1H), 7.75 (d, 1H), 8.1 (d, 1H).

[1068] A mixture of a portion (1 g) of the material so obtained,diphenylphosphoryl azide 2.2 ml), triethylamine (1.4 ml) andtert-butanol (2.7 ml) was stirred and heated to reflux for 18 hours. Themixture was allowed to cool to ambient temperature, poured into waterand extracted with ethyl acetate. The organic phase was washed in turnwith water and brine, dried over magnesium sulphate and evaporated. Theresidue was purified by column chromatography on alumina usingincreasingly polar solvent mixtures starting with mixtures of petroleumether and methylene chloride and ending with a 4:1 mixture of methylenechloride and ethyl acetate. There was thus obtained a mixture of7-amino-6-chlorobenzofuran and tert-butyl6-chlorobenzofuran-7-carbamate. A solution of the mixture so obtained inmethylene chloride (15 ml) was cooled to 0°C. and trifluoroacetic acid(1.2 ml) was added. The resultant mixture was stirred for 1 hour. Themixture was evaporated and the residue was partitioned between ethylacetate and a saturated aqueous sodium bicarbonate solution. The organicphase was dried over magnesium sulphate and evaporated. The residue waspurified by column chromatography on silica using a 3:1 mixture ofpetroleum ether (b.p. 60-80° C.) and methylene chloride as eluent. Therewas thus obtained 7-amino-6-chlorobenzofuran (0.376 g); NMR Spectrum:(DMSOd₆) 5.5 (br s, 2H), 6.85 (m, 2H), 7.1 (d, 1H), 7.95 (d, 1H); MassSpectrum: M+H⁺ 167.

EXAMPLE 484-(3-chlorobenzofuran-7-ylamino)-7-(2-pyrrolidin-1-ylethoxy)-5-cyclopentyloxyquinazolinedihydrochloride

[1069] Using an analogous procedure to that described in Example 47,4-chloro-5-cyclopentyloxy-7-(2-pyrrolidin-1-ylethoxy)quinazoline (0.1 g)was reacted with 7-amino-3-chlorobenzofuran (0.051 g) to give the titlecompound, as a dihydrochloride salt (0.074 g), a portion of which wasconverted into the free base using an analogous procedure to thatdescribed in Example 3. The free base gave the following characterisingdata: NMR Spectrum: (CDCl₃) 1.7-1.8 (m, 2H), 1.8-2.0 (m, 6H), 2.1-2.3(m, 4H), 2.7 (br s, 4H), 3.02 (m, 2H), 4.3 (t, 2H), 5.08 (m, 1H), 6.61(d, 1H), 6.84 (d, 1H), 7.3-7.45 (m, 2H), 7.65 (s, 1H), 8.64 (s, 1H),8.76 (d, 1H), 10.3 (s, 1H); Mass Spectrum: M+H⁺ 493 and 495.

EXAMPLE 494-(2-chloro-5-methoxyanilino)-5-(4-methylpiperazin-1-yl)-7-(2-pyrrolidin-1-ylethoxy)quinazolinetrihydrochloride

[1070] Using an analogous procedure to that described in Example 5,4-chloro-5-(4-methylpiperazin-1-yl)-7-(2-pyrrolidin-1-ylethoxy)quinazoline(0.11 g) was reacted with 2-chloro-5-methoxyaniline hydrochloride (0.064g) in the presence of a 6M solution of hydrogen chloride in isopropanol(0.05 ml) to give the title compound, as a trihydrochloride salt (0.092g), a portion of which was converted into the free base using ananalogous procedure to that described in Example 3. The free base gavethe following characterising data: NMR Spectrum: (CDCl₃) 1.8-1.9 (m,4H), 2.32 (s, 3H), 2.48 (m, 2H), 2.65 (br s, 4H), 2.82 (d, 2H), 2.98 (m,4H), 3.2 (d, 2H), 3.82 (s, 3H), 4.25 (m, 2H), 6.65 (m, 1H), 6.95 (m,1H), 7.3 (d, 1H), 8.02 (d, 1H), 8.52 (s, 1H); Mass Spectrum: M+H⁺ 497and 499.

[1071] The4-chloro-5-(4-methylpiperazin-1-yl)-7-(2-pyrrolidin-1-ylethoxy)quinazolineused as a starting material was prepared as follows:

[1072] A mixture of 5,7-difluoro-3,4-dihydroquinazolin-4-one (0.091 g),1-methylpiperazine (0.1 g) and DMF (2 ml) was stirred and heated to 100°C. for 1 hour. The mixture was evaporated and the residue was purifiedby column chromatography using a 97:3 mixture of methylene chloride anda saturated methanolic ammonia solution as eluent. There was thusobtained 7-fluoro-5-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one(0.09 g); NMR Spectrum: (CDCl₃) 2.42 (s, 3H), 2.72 (br s, 4H), 3.2 (brs, 4H), 6.72 (m, 1H), 7.0 (m, 1H), 8.0 (s, 1H); Mass Spectrum: M+H⁺ 263.

[1073] Sodium hydride (60% dispersion in mineral oil; 0.96 g) was addedto a stirred solution of 1-(2-hydroxyethyl)pyrrolidine (1.4 ml) in DMF(20 ml) and the mixture was stirred at ambient temperature for 10minutes. 7-Fluoro-5-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one(0.09 g) was added and the mixture was stirred and heated to 100° C. for3 hours. The resultant mixture was evaporated and acetic acid (1.4 ml)and methylene chloride were added in turn to the residue. The mixturewas filtered and the filtrate was poured onto a column of silica andeluted with a 19:1 mixture of methylene chloride and a saturatedmethanolic ammonia solution. The material so obtained as trituratedunder pentane, isolated, washed with pentane and dried under vacuum.There was thus obtained5-(4-methylpiperazin-1-yl)-7-(2-pyrrolidin-1-ylethoxy)-3,4-dihydroquinazolin-4-one(0.74 g); NMR Spectrum: (CDCl₃) 1.7-1.9 (m, 4H), 2.4 (s, 3H), 2.6-2.8(m, 8H), 2.92 (t, 2H), 3.15 (br s, 4H), 4.2 (t, 2H), 6.6 (d, 1H), 6.8(d, 1H), 7.92 (s, 1H); Mass Spectrum: M+H⁺ 358.

[1074] A mixture of a portion (0.65 g) of the material so obtained,phosphoryl chloride (0.252 ml), diisopropylethylamine (0.94 ml) and1,2-dichloroethane (30 ml) was stirred and heated to 80° C. for 2 hours.The mixture was evaporated and the residue was purified by columnchromatography on silica using a 24:1 mixture of methylene chloride anda saturated methanolic ammonia solution as eluent. There was thusobtained4-chloro-5-(4-methylpiperazin-1-yl)-7-(2-pyrrolidin-1-ylethoxy)quinazoline(0.23 g); NMR Spectrum: (CDCl₃) 1.9-2.1 (br s, 4H), 2.5 (s, 3H), 2.65(m, 2H), 2.85-3.1 (m, 10H), 3.32 (d, 2H), 4.4 (br s, 2H), 6.85 (d, 1H),7.05 (d, 1H), 8.8 (s, 1H); Mass Spectrum: M+H⁺ 376.

EXAMPLE 504-(6-chloro-2,3-methylenedioxyanilino)-5-(N-methylpiperidin-4-yloxy)-7-(2,2,2-trifluoroethoxy)quinazoline

[1075] A mixture of4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-(N-methylpiperidin-4-yloxy)quinazoline(0.1 g), 2,2,2-trifluoroethyl 4-toluenesulphonate (0.071 g), potassiumcarbonate (0.08 g) and DMF (2 ml) was stirred and heated to 95° C. for24 hours. The mixture was cooled to ambient temperature and partitionedbetween ethyl acetate and water. The organic solution was washed withwater and with brine, dried over magnesium sulphate and evaporated Theresidue was purified by column chromatography on silica using a 45:46:4mixture of methylene chloride, ethyl acetate and methanol as eluent.There was thus obtained the title compound (0.058 g); NM: Spectrum:(CDCl₃) 1.95-2.1 (m, is 2H), 2.1-2.3 (m, 2H), 2.32 (s, 3H), 2.3-2.45 (m,2H), 2.75 (m, 2H), 4.48 (m, 2H), 4.64 (m, 1H), 6.05 (s, 2H), 6.6 (d,1H), 6.74 (d, 1H), 6.78 (d, 1H), 6.97 (d, 1H), 8.5 (s, 1H), 9.28 (s,1H); Mass Spectrum: M+H⁺ 511 and 513.

[1076] The4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-(N-methylpiperidin-4-yloxy)quinazolineused as a starting material was prepared as follows:

[1077] A solution of di-tert-butyl azodicarboxylate (5.44 g) inmethylene chloride (20 ml) was added dropwise to a stirred mixture of7-benzyloxy-5-hydroxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (6g) 4-hydroxy-N-methylpiperidine (2.17 g), triphenylphosphine (6.17 g)and methylene chloride (100 ml) that had been cooled to 0° C. Theresultant mixture was stirred at ambient temperature for 1 hour. Themixture was evaporated and the residue was purified by columnchromatography on silica using a 10:9:1 mixture of methylene chloride,ethyl acetate and a saturated methanolic ammonia solution as eluent. Thematerial so obtained was dissolved in a saturated methanolic ammoniasolution (240 ml) and stirred at ambient temperature for 16 hours. Themixture was evaporated and the residue was triturated under diethylether. The resultant solid was isolated, washed with diethyl ether anddried under vacuum. There was thus obtained7-benzyloxy-5-(N-methylpiperidin-4-yloxy)-3,4-dihydroquinazolin-4-one(3.68 g); NMR Spectrum: (CDCl₃) 2.0 (m, 4H), 2.3 (s, 3H), 2.35 (m, 2H),2.75 (m, 2H), 4.5 (m, 1H), 5.15 (s, 2H), 6.6 (d, 1H), 6.82 (d, 1H),7.3-7.5 (m, 5H), 7.92 (s, 1H); Mass Spectrum: M+H⁺ 366.

[1078] A mixture of the material so obtained, triphenylphosphine (8.65g), carbon tetrachloride (10 ml) and 1,2-dichloroethane (100 ml) wasstirred and heated to 70° C. for 2 hours. The mixture was evaporated andthe 7-benzyloxy-4-chloro-5-(N-methylpiperidin-4-yloxy)quinazoline soobtained was dissolved in isopropanol (2 ml) and6-chloro-2,3-methylenedioxyaniline (1.9 g) and a 5M hydrogen chloridesolution in isopropanol (2.1 ml) were added in turn. The resultantmixture was stirred at 50° C. for 20 minutes and at 80° C. for 30minutes. The mixture was evaporated and the residue was suspended inethyl acetate and stirred for 1 hour at ambient temperature. Theresultant solid was isolated, washed with ethyl acetate and with diethylether. The solid was dissolved in a 19:1 mixture of methylene chlorideand a saturated methanolic ammonia solution and stirred at ambienttemperature for 15 minutes. The mixture was filtered, the filtrate wasevaporated and the residue was purified by column chromatography onsilica using a 50:47:3 mixture of ethyl acetate, methylene chloride andmethanol as eluent. There was thus obtained7-benzyloxy-4-chloro-5-(N-methylpiperidin-4-yloxy)quinazoline (4.2 g);NMR Spectrum:(CDCl₃) 2.0-2.1 (m, 2H), 2.2 (m, 2H), 2.3 (s, 3H),2.25-2.35 (m, 2H), 2.75 (m, 2H), 4.6 (m, 1H), 5.2 (s, 2H), 6.1 (s, 2H),6.6 (s, 1H), 6.75 (d, 1H), 6.95 (s, 1H), 7.0 (d, 1H), 7.32-7.52 (m, 5H),8.52 (s, 1H), 9.3 (s, 1H); Mass Spectrum: M+H⁺ 519 and 521.

[1079] A mixture of a portion (1.5 g) of the material so obtained andtrifluoroacetic acid (15 ml) was stirred and heated to reflux for 6hours. The mixture was evaporated and the residue was dissolved in waterand basified to pH9 by the addition of solid sodium bicarbonate. Themixture was extracted with ethyl acetate and the organic layer waswashed with brine, dried over magnesium sulphate and evaporated. Theresidue was purified by column chromatography on silica using a 10:9:2mixture of ethyl acetate, methylene chloride and methanol as eluent.There was thus obtained4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-(n-methylpiperidin-4-yloxy)quinazoline(0.8 g); NMR Spectrum: (CDCl₃) 1.9-2.05 (m, 2H), 2.05-2.15 (m, 2H),2.2-2.3 (m, 2H), 2.28 (s, 3H), 2.7 (m, 2H), 4.5 (br s, 1H), 6.05 (s,2H), 6.5 (d, 1H), 6.7 (d, 1H), 6.85 (d, 1H), 6.95 (d, 1H), 8.4 (s, 1H),9.35 (s, 1H); Mass Spectrum M+H⁺ 429 and 431.

EXAMPLE 514-(6-chloro-2,3-methylenedioxyanilino)-7-ethoxy-5-(N-methylpiperidin-4-yloxy)quinazoline

[1080] A solution of di-tert-butyl azodicarboxylate (0.26 g) inmethylene chloride (1 ml) was added dropwise to a stirred mixture of4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-(N-methylpiperidin-4-yloxy)quinazoline(0.12 g), ethanol (0.019 g), triphenylphosphine (0.15 g) and methylenechloride (2 ml) and the resultant mixture was stirred at ambienttemperature for 1 hour. A 2M solution of hydrogen chloride in diethylether (3 ml) was added and the mixture was stirred at ambienttemperature for 1.5 hours. Diethyl ether (1 ml) was added and theprecipitate was isolated and dried under vacuum. The solid so obtainedwas dissolved in a 9:1 mixture of methylene chloride and a saturatedmethanolic ammonia solution. The mixture was filtered and the filtratewas evaporated. The residue was triturated under pentane and theresultant solid was isolated and dried under vacuum. There was thusobtained the title compound (0.092 g); NMR Spectrum: (CDCl₃) 1.5 (t,3H), 1.95-2.1 (m, 2H), 2.15-2.5 (m, 2H), 2.3 (s, 3H), 2.3-2.4 (m,2-2),2.7 (br s, 2H), 4.15 (m, 2H), 4.6 (m, 1H), 6.05 (s, 2H), 6.5 (d, 1H),6.7 (d, 1H), 6.8 (d, 1H), 6.95 (d, 1H), 8.5 (s, 1H), 9.25 (br s, 1H);Mass Spectrum: M+H⁺ 457 and 459.

EXAMPLE 524-(6-chloro-2,3-methylenedioxyanilino)-7-(2-fluoroethoxy)-5-(N-methylpiperidin-4-yloxy)quinazoline

[1081] Using an analogous procedure to that described in Example 51,4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-(N-methylpiperidin-4-yloxy)quinazolinewas reacted with 2-fluoroethanol to give the title compound; NMRSpectrum: (CDCl₃) 2.0-2.1 (m, 2H), 2.15-2.3 (m, 2H), 2.35 (s, 3H),2.3-2.4 (m, 2H), 2.8 (br s, 2H), 4.32 (m, 1H), 4.4 (m, 1H), 4.65 (m,1H), 4.8 (m, 1H), 4.9 (m, 1H), 6.05 (s, 2H), 6.6 (s, 1H), 6.75 (d, 1H),6.85 (s, 1H), 7.0 (d, 1H), 8.55 (s, 1H), 9.3 (s, 1H); Mass Spectrum:M+H⁺ 475 and 477.

EXAMPLE 534-(6-chloro-2,3-methylenedioxyanilino)-7-isobutoxy-5-(N-methylpiperidin-4-yloxy)quinazoline

[1082] Using an analogous procedure to that described in Example 51,4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-(N-methylpiperidin-4-yloxy)quinazolinewas reacted with isobutanol to give the title compound; NMR Spectrum:(CDCl₃) 1.05 (d, 6H), 1.95-2.05 (m, 2H), 2.08-2.28 (m, 3H), 2.3 (s, 3H),2.3-2.4 (m, 2H), 2.7 (br s, 2H), 3.82 (d, 2H), 4.6 (m, 1H), 6.03 (s,2H), 6.5 (s, 1H), 6.7 (d, 1H), 6.8 (s, 1H), 6.95 (d, 1H), 8.5 (s, 1H),9.25 (s, 1H); Mass Spectrum: M+H⁺ 485 and 487.

EXAMPLE 544-(2,3-methylenedioxyanilino)-5-(4-methylpiperazin-1-yl)-7-(2-pyrrolidin-1-ylethoxy)quinazolinetrihydrochloride

[1083] Using an analogous procedure to that described in Example 5,4-chloro-5-(4-methylpiperazin-1-yl)-7-(2-pyrrolidin-1-ylethoxy)quinazoline(0.11 g) was reacted with 2,3-methylenedioxyaniline (0.045 g) in thepresence of a 6M solution of hydrogen chloride in isopropanol to givethe title compound, as a trihydrochloride salt (0.105 g), a portion ofwhich was converted into the free base using an analogous procedure tothat described in Example 3. The free base gave the followingcharacterising data: NMR Spectrum: (CDCl₃) 1.78 (br s, 4H), 2.3 (s, 3H),2.5 (m, 2H), 2.6 (br s, 4H), 2.8 (d, 2H), 2.95 (m, 4H), 3.08 (d, 2H),4.18 (m, 2H), 5.98 (s, 2H), 6.6 (d, 1H), 6.86 (m, 1H), 6.94 (s, 1H),8.06 (d, 1H), 8.5 (s, 1H), 11.8 (s, 1H); Mass Spectrum: M+H⁺ 477.

EXAMPLE 554-(6-chloro-2,3-methylenedioxyanilino)-5-morpholino-7-(2-pyrrolidin-1-ylethoxy)quinazoline

[1084] A mixture of4-chloro-5-morpholino-7-(2-pyrrolidin-1-ylethoxy)quinazoline (0.27 g),6-chloro-2,3-methylenedioxyanline (0.14 g) and isopropanol (4 ml) wasstirred and heated to 80° C. for 1 hour. The mixture was evaporated andthe residue was dissolved in a 49:1 mixture of methylene chloride and asaturated methanolic ammonia solution. The mixture was filtered and thefiltrate was poured onto a column of silica and eluted with a 97:3mixture of methylene chloride and a saturated methanolic ammoniasolution. The material so obtained was triturated under diethyl ether.The resultant solid was isolated, washed with diethyl ether and driedunder vacuum. There was thus obtained the title compound (0.035 g); NMRSpectrum: (CDCl₃) 1.85 (br s, 4H), 2.65 (br s, 4H), 3.0 (m, 2H), 3.08(m, 2H), 3.18 (d, 2H), 3.82 (m, 2H), 4.05 (m, 2H), 4.25 (m, 2H), 6.05(s, 2H), 6.75 (d, 1H), 6.95-7.1 (m, 3H), 8.52 (s, 1H); Mass Spectrum:M+H⁺ 498 and 500.

[1085] The 4-chloro-5-morpholino-7-(2-pyrrolidin-1-ylethoxy)quinazolineused as a starting material was prepared as follows:

[1086] A mixture of 5,7-difluoro-3,4-dihydroquinazolin-4-one (0.91 g),morpholine (0.9 ml) and DMF (20 ml) was stirred and heated to 100° C.for 1 hour. The mixture was evaporated. A saturated methanolic ammoniasolution (1 ml) was added to the residue and the mixture was stirred atambient temperature for 5 minutes. The mixture was evaporated and theresidue was triturated under water. The resultant solid was isolated,washed with water and with diethyl ether and dried under vacuum. Therewas thus obtained 7-fluoro-5-morpholino-3,4-dihydroquinazolin-4-one(0.85 g); NMR Spectrum: (DMSOd₆) 3.05 (br s, 4H), 3.8 (t, 4H), 6.8 (m,1H), 6.92 (m, 1H), 8.02 (s, 1H); Mass Spectrum: M+H⁺ 250.

[1087] Sodium hydride (60% dispersion in mineral oil, 0.5 g) was addedto a stirred solution of 1-(2-hydroxyethyl)pyrrolidine (0.7 ml) in DMF(15 ml) which had been cooled to 5° C. The mixture was stirred for 10minutes. 7-Fluoro-5-morpholino-3,4-dihydroquinazolin-4-one (0.75 g) wasadded and the mixture was heated to 80° C. for 1 hour and then to 90° C.for 3 hours. The mixture was evaporated and the residue was dissolved inacetic acid (0.9 ml) and diluted with a mixture of methylene chlorideand methanol. The resultant solution was poured onto a column of silicaand eluted with a 47:3 mixture of methylene chloride and methanol aseluent. The material so obtained was triturated under diethyl ether andthe resultant solid was isolated, washed with diethyl ether and driedunder vacuum. There was thus obtained5-morpholino-7-(2-pyrrolidin-1-ylethoxy)-3,4-dihydroquinazolin-4-one(0.5 g); NMR Spectrum: (DMSOd₆) 1.7 (br s, 4H), 2.8 (m, 2H), 3.02 (br s,4H), 3.8 (m, 4H), 4.2 (m, 2m), 6.45 (d, 1H), 6.7 (d, 1H), 7.92 (s, 1H),11.7 (br s, 1H); Mass Spectrum: M+H⁺ 345.

[1088] A mixture of a portion (0.26 g) of the material so obtained,phosphoryl chloride (0.084 ml), diisopropylethylamine (0.34 ml) and1,2-dichloroethane (5 ml) was stirred and heated to 80° C. for 3 hours.The mixture was evaporated to give4-chloro-5-morpholino-7-(2-pyrrolidin-1-ylethoxy)quinazoline which wasused without further purification.

EXAMPLE 56 4-(6-chloro-2,3-methylenedioxyanilino)-5-phenoxyquinazolinemonohydrochloride

[1089] A mixture of4-(6-chloro-2,3-methylenedioxyanilino)-5-fluoroquinazoline (0.213 g),phenol (0.45 g), potassium carbonate (0.828 g) and DMF (3 ml) wasstirred and heated to 90° C. for 30 hours. The mixture was evaporatedand the residue was partitioned between ethyl acetate and a 2N aqueoussodium hydroxide solution. The organic layer was washed with brine,dried over magnesium sulphate and evaporated. The residue was purifiedby column chromatography on silica using a 99:1 mixture of methylenechloride and methanol as eluent. The material so obtained was dissolvedin diethyl ether and a 6M solution of hydrogen chloride in diethyl ether(1 equivalent) was added. The resultant solid was isolated, washed withdiethyl ether and dried under vacuum. There was thus obtained the titlecompound (0.05 g); NMR Spectrum: (DMSOd₆ and CF₃CO₂D) 6.18 (s, 2H), 6.95(d, 1H), 7.05 (d, 1H), 7.1 (d, 1H), 7.35 (d, 1H), 7.42 (m, 1H),7.52-7.62 (m, 3H), 8.0 (m, 1H), 9.0 (s, 1H); Mass Spectrum: M+H⁺ 392 and394.

EXAMPLE 57

[1090] Pharmaceutical Compositions

[1091] The following illustrate representative pharmaceutical dosageforms of the invention as defined herein (the active ingredient beingtermed “Compound X”), for therapeutic or prophylactic use in humans: (a)Tablet I mg/tablet Compound X 100 Lactose Ph.Eur 182.75 Croscarmellosesodium 12.0 Maize starch paste (5% w/v paste) 2.25 Magnesium stearate3.0 (b) Tablet II mg/tablet Compound X 50 Lactose Ph.Eur 223.75Croscarmellose sodium 6.0 Maize starch 15.0 Polyvinylpyrrolidone (5% w/vpaste) 2.25 Magnesium stearate 3.0 (c) Tablet III mg/tablet Compound X1.0 Lactose Ph.Eur 93.25 Croscarmellose sodium 4.0 Maize starch paste(5% w/v paste) 0.75 Magnesium stearate 1.0 (d) Capsule mg/capsuleCompound X 10 Lactose Ph.Eur 488.5 Magnesium 1.5 (e) Injection I (50mg/ml) Compound X  5.0% w/v 1M Sodium hydroxide solution 15.0% v/v 0.1MHydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400  4.5%w/v Water for injection to 100% (f) Injection II (10 mg/ml) Compound X 1.0% w/v Sodium phosphate BP  3.6% w/v 0.1M Sodium hydroxide solution15.0% v/v  Water for injection to 100% (g) Injection III (1 mg/ml,buffered to pH6) Compound X  0.1% w/v Sodium phosphate BP 2.26% w/vCitric acid 0.38% w/v Polyethylene glycol 400  3.5% w/v Water forinjection to 100% (h) Aerosol I mg/ml Compound X 10.0 Sorbitan trioleate13.5 Trichlorofluoromethane 910.0 Dichlorodifluoromethane 490.0 (i)Aerosol II mg/ml Compound X 0.2 Sorbitan trioleate 0.27Trichlorofluoromethane 70.0 Dichlorodifluoromethane 280.0Dichlorotetrafluoroethane 1094.0 (j) Aerosol III mg/ml Compound X 2.5Sorbitan trioleate 3.38 Trichlorofluoromethane 67.5Dichlorodifluoromethane 1086.0 Dichlorotetrafluoroethane 191.6 (k)Aerosol IV mg/ml Compound X 2.5 Soya lecithin 2.7 Trichlorofluoromethane67.5 Dichlorodifluoromethane 1086.0 Dichlorotetrafluoroethane 191.6 (l)Ointment ml Compound X  40 mg Ethanol 300 μl Water 300 μl1-Dodecylazacycloheptan-2-one  50 μl Propylene glycol to 1 ml#suspending agent such as sorbitan monooleate, sorbitan sesquioleate,polysorbate 80, polyglycerol oleate or oleic acid.

1. A quinazoline derivative of the Formula I

wherein m is 0, 1, 2 or 3; each R¹ group, which may be the same ordifferent, is selected from halogeno, trifluoromethyl, cyano, isocyano,nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl,(1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy,(2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,(3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino,(3-6C)alkynoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino,N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,(1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,or from a group of the formula: Q³—X¹—  wherein X¹ is a direct bond oris selected from O, S, SO, SO₂, N(R⁴), CO, CH(OR⁴), CON(R⁴), N(R⁴)CO,SO₂N(R⁴), N(R⁴)SO₂, OC(R⁴)₂, SC(R⁴)₂ and N(R⁴)C(R⁴)₂, wherein R⁴ ishydrogen or (1-6C)alkyl, and Q³ is aryl, aryl-(1-6C)alkyl,(3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl, or (R¹)_(m) is(1-3C)alkylenedioxy, and wherein adjacent carbon atoms in any(2-6C)alkylene chain within a R¹ substituent are optionally separated bythe insertion into the chain of a group selected from O, S, SO, SO₂,N(R⁵), CO, CH(OR⁵), CON(R⁵), N(R⁵)CO, SO₂N(R⁵), N(R⁵)SO₂, CH═CH and C≡Cwherein R⁵ is hydrogen or (1-6C)alkyl, and wherein any CH₂═CH— or HC≡C—group within a R¹ substituent optionally bears at the terminal CH₂═ orHC≡ position a substituent selected from halogeno, carboxy, carbamoyl,(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl orfrom a group of the formula: Q⁴-X²—  wherein X² is a direct bond or isselected from CO and N(R⁶)CO, wherein R⁶ is hydrogen or (1-6C)alkyl, andQ⁴ is aryl, aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any CH₂ or CH₃group within a R¹ substituent optionally bears on each said CH₂ or CH₃group one or more halogeno or (1-6C)alkyl substituents or a substituentselected from hydroxy, cyano, amino, carboxy, carbamoyl, (1-6C)alkoxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,(2-6C)alkanoyloxy, (2-6C)alkanoylamino,N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl,N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino andN-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of theformula: —X³-Q⁵  wherein X³ is a direct bond or is selected from O, S,SO, SO₂, N(R⁷), CO, CH(OR⁷), CON(R⁷), N(R⁷)CO, SO₂N(R⁷), N(R⁷)SO₂,C(R⁷)₂O, C(R⁷)₂S and N(R⁷)C(R⁷)₂, wherein R⁷ is hydrogen or (1-6C)alkyl,and Q⁵ is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any aryl,heteroaryl or heterocyclyl group within a substituent on R¹ optionallybears 1, 2 or 3 substituents, which may be the same or different,selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino,carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl,(1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,(1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,or from a group of the formula: —X⁴—R⁸  wherein X⁴ is a direct bond oris selected from O and N(R⁹), wherein R⁹ is hydrogen or (1-6C)alkyl, andR⁸ is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl,(1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl,(2-6C)alkanoylamino-(1-6C)alkyl or(1-6C)alkoxycarbonylamino-(1-6C)alkyl, or from a group of the formula:—X⁵-Q⁶  wherein X⁵ is a direct bond or is selected from O, CO andN(R¹⁰), wherein R¹⁰ is hydrogen or (1-6C)alkyl, and Q⁶ is aryl,aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from halogeno, (1-6C)alkyland (1-6C)alkoxy, and wherein any heterocyclyl group within asubstituent on R¹ optionally bears 1 or 2 oxo or thioxo substituents; R²is hydrogen or (1-6C)alkyl; R³ is hydrogen or (1-6C)alkyl; Z is a directbond or is selected from O, S, SO, SO₂, N(R¹¹), CO, CH(OR¹¹), CON(R¹¹),N(R¹¹)CO, SO₂N(R¹¹), N(R¹¹)SO₂, OC(R¹¹)₂, SC(R¹¹)₂ and N(R¹¹)C(R¹¹)₂, wherein R¹¹is hydrogen or (1-6C)alkyl; Q¹ is aryl, aryl-(1-6C)alkyl,(3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl, or, when Z is a direct bond orO, Q¹ may be (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl,halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl,cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(1-6C)alkyl, (1-6C)alkylthio-(1-6C)alkyl,(1-6C)alkylsulphinyl-(1-6C)alkyl or (1-6C)alkylsulphonyl-(1-6C)alkyl,and wherein adjacent carbon atoms in any (2-6C)alkylene chain within theQ¹-Z— group are optionally separated by the insertion into the chain ofa group selected from O, S, SO, SO₂, N(R¹²), CO, CH(OR¹²), CON(R¹²),N(R¹²)CO, SO₂N(R¹²), N(R¹²)SO₂, CH═CH and C≡C wherein R¹² is hydrogen or(1-6C)alkyl, and wherein any CH₂═CH— or HC≡C— group within the Q¹-Z—group optionally bears at the terminal CH₂═ or HC≡ position asubstituent selected from halogeno, carboxy, carbamoyl,(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl orfrom a group of the formula: Q⁷-X⁶—  wherein X⁶ is a direct bond or isselected from CO and N(R¹³)CO, wherein R¹³ is hydrogen or (1-6C)alkyl,and Q⁷ is aryl, aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any CH₂ or CH₃group within the Q¹-Z— group optionally bears on each said CH₂ or CH₃group one or more halogeno or (1-6C)alkyl substituents or a substituentselected from hydroxy, cyano, amino, carboxy, carbamoyl, (1-6C)alkoxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,(2-6C)alkanoyloxy, (2-6C)alkanoylamino,N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl,N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino andN-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of theformula: —X⁷-Q⁸  wherein X⁷ is a direct bond or is selected from O, S,SO, SO₂, N(R¹⁴), CO, CH(OR¹⁴), CON(R¹⁴), N(R¹⁴)CO, SO₂N(R¹⁴), N(R¹⁴)SO₂,C(R¹⁴)₂O, C(R¹⁴)₂S and N(R¹⁴)C¹⁴)₂, wherein R¹⁴ is hydrogen or(1-6C)alkyl, and Q⁸ is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any aryl,heteroaryl or heterocyclyl group within the Q¹-Z— group optionally bears1, 2 or 3 substituents, which may be the same or different, selectedfrom halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy,carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy,(2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,(1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,or from a group of the formula: —X⁸—R¹⁵  wherein X⁸ is a direct bond oris selected from O and N(R¹⁶), wherein R¹⁶ is hydrogen or (1-6C)alkyl,and R¹⁵ is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl,(1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl or di-[(1-6C)alkyl]amino-(1-6C)alkyl, orfrom a group of the formula: —X⁹-Q⁹  wherein X⁹ is a direct bond or isselected from O, CO and N(R¹⁷), wherein R¹⁷ is hydrogen or (1-6C)alkyl,and Q⁹ is aryl, aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl which optionally bears 1 or 2substituents, which may be the same or different, selected fromhalogeno, (1-6C)alkyl and (1-6C)alkoxy, and wherein any heterocyclylgroup within the Q¹-Z— group optionally bears 1 or 2 oxo or thioxosubstituents; and Q² is an aryl group of formula Ia

 wherein G¹ is selected from halogeno, trifluoromethyl, cyano, nitro,hydroxy, amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl,(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,(2-6C)alkanoyloxy, (2-6C)alkanoylamino,N-(1-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino,N-(1-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino,N-(1-6C)alkyl-(3-6C)alkynoylamino, N-(1-6C)alkylsulphamoyl,N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino andN-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of theformula: —X¹⁰—R¹⁸  wherein X¹⁰ is a direct bond or is selected from Oand N(R¹⁹), wherein R¹⁹ is hydrogen or (1-6C)alkyl, and R¹⁸ ishalogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl,cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl ordi-[(1-6C)alkyl]amino-(1-6C)alkyl, or from a group of the formula:—X¹¹-Q¹⁰  wherein X¹¹ is a direct bond or is selected from O, S, SO,SO₂, N(R²⁰), CO, CH(OR²⁰), CON(R²⁰), N(R²⁰)CO, SO₂N(R²⁰), N(R²⁰)SO₂,C(R²⁰)₂O, C(R²⁰)₂S and N(R²⁰)C(R²⁰)₂, wherein R²⁰ is hydrogen or(1-6C)alkyl, and Q¹⁰ is aryl, aryl-(1-6C)alkyl, heteroaryl,heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl whichoptionally bears 1 or 2 substituents, which may be the same ordifferent, selected from halogeno, (1-6C)alkyl and (1-6C)alkoxy, and anyheterocyclyl group within Q¹⁰ optionally bears 1 or 2 oxo or thioxosubstituents, and each of G², G³, G⁴ and G⁵, which may be the same ordifferent, is selected from hydrogen, halogeno, trifluoromethyl, cyano,nitro, hydroxy, amino, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl,(1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, or G¹ and G²together form a group of formula: —CH═CH—CH═CH—, —N═CH—CH═CH—,—CH═N—CH═CH—, —CH═CH—N═CH—, —CH═CH—CH═N—, —N═CH—N═CH—, —CH═N—CH═N—,—N═CH—CH═N—, —N═N—CH═CH—, —CH═CH—N═N—, —CH═CH—O—, —O—CH═CH—, —CH═CH—S—,—S—CH═CH—, —CH₂—CH₂—O—, —O—CH₂—CH₂—, —CH₂—CH₂—S—, —S—CH₂—CH₂—,—O—CH₂—O—, —O—CH₂—CH₂—O—, —S—CH₂—S—, —S—CH₂—CH₂—S—, —CH═CH—NH—,—NH—CH═CH—, —CH₂—CH₂—NH—, —NH—CH₂—CH₂—, —N═CH—NH—, —NH—CH═N—,—NH—CH₂—NH—, —O—CH═N—, —N═CH—O—, —S—CH—═N—, —N═CH—S—, —O—CH₂—NH—,—NH—CH₂—O—, —S—CH₂—NH—, —NH—CH₂—S—, —O—N═CH—, —CH═N—O—, —S—N═CH—,—CH═N—S—, —O—NH—CH₂—, —CH₂—NH—O—, —S—NH—CH₂—, —CH₂—NH—S—, —NH—N═CH—,—CH═N—NH—, —NH—NH—CH₂—, —CH₂—NH—NH—, —N═N—NH— or —NH—N═N—, or G¹ has anyof the meanings defined hereinbefore and G² and G³ together or G³ and G⁴together form a group of formula: —CH═CH—CH═CH—, —N═CH—CH═CH—,—CH═N—CH═CH—, —CH═CH—N═CH—, —CH═CH—CH═N—, —N═CH—N═CH—, —CH═N—CH═N—,—N═CH—CH═N—, —N═N—CH═CH—, —CH═CH—N═N—, —CH═CH—O—, —O—CH═CH—, —CH═CH—S—,—S—CH═CH—, —CH₂—CH₂—O—, —O—CH₂—CH₂—, —CH₂—CH₂—S—, —S—CH₂—CH₂—,—O—CH₂—O—, —O—CH₂—CH₂—O—, —S—CH₂—S—, —S—CH₂—CH₂—S—, —CH═CH—NH—,—NH—CH═CH—, —CH₂—CH₂—NH—, —NH—CH₂—CH₂—, —N═CH—NH—, —NH—CH═N—,—NH—CH₂—NH—, —O—CH═N—, —N═CH—O—, —S—CH═N—, —N═CH—S—, —O—CH₂—NH—,—NH—CH₂—O—, —S—CH₂—NH—, —NH—CH₂—S—, —O—N═CH—, —CH═N—O—, —S—N═CH—,—CH═N—S—, —O—NH—CH₂—, —CH₂—NH—O—, —S—NH—CH₂—, —CH₂—NH—S—, —NH—N═CH—,—CH═N—NH—, —NH—NH—CH₂—, —CH₂—NH—NH—, —N═N—NH— or —NH—N═N—, and the 9- or10-membered bicyclic heteroaryl or heterocyclic ring formed when G¹ andG² together, G² and G³ together or G³ and G⁴ together are linkedoptionally bears on the heteroaryl or heterocyclic portion of thebicyclic ring 1, 2 or 3 substituents, which may be the same ordifferent, selected from halogeno, trifluoromethyl, cyano, nitro,hydroxy, amino, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy,(1-6C)alkylamino and di-[(1-6C)alkyl]amino, and any bicyclicheterocyclic ring so formed optionally bears 1 or 2 oxo or thioxogroups; or a pharmaceutically-acceptable salt thereof.
 2. A quinazolinederivative of the Formula I according to claim 1, or apharmaceutically-acceptable salt thereof, wherein each of m, R¹, R², R³and Q² has any of the meanings defined in claim 1 and Z is a direct bondor is selected from O, S, SO, SO₂, N(R¹¹), CO, CH(OR¹¹), CON(R¹¹),N(R¹¹)CO, SO₂N(R¹¹), N(R¹¹)SO₂, OC(R¹¹)₂, SC(R¹¹)₂ and N(R¹¹)C(R¹¹)₂,wherein R¹¹ is hydrogen or (1-6C)alkyl; and Q¹ is aryl,aryl-(1-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl,(3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl,heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, andwherein adjacent carbon atoms in any (2-6C)alkylene chain within theQ¹-Z— group are optionally separated by the insertion into the chain ofa group selected from O, S, SO, SO₂, N(R¹²), CO, CH(OR¹²), CON(R¹²),N(R¹²)CO, SO₁₂N(R¹²), N(R²)SO₂, CH═CH and C≡C wherein R¹² is hydrogen or(1-6C)alkyl, and wherein any CH₂ or CH₃ group within the Q¹-Z— groupoptionally bears on each said CH₂ or CH₃ group one or more halogeno or(1-6C)alkyl substituents or a substituent selected from hydroxy, cyano,amino, carboxy, carbamoyl, (1-6C)alkoxy, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,(1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,or from a group of the formula: —X⁷-Q⁸  wherein X⁷ is a direct bond oris selected from O, S, SO, SO₂, N(R¹⁴), CO, CH(OR¹⁴), CON(R¹⁴),N(R¹⁴)CO, SO₂N(R¹⁴), N(R¹⁴)SO₂, C(R¹⁴)₂O, C(R¹⁴)₂S and N(R¹⁴)C(R¹⁴)₂, wherein R¹⁴ is hydrogen or (1-6C)alkyl, and Q⁸ is aryl,aryl-(1-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl,(3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl,heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, andwherein any aryl, heteroaryl or heterocyclyl group within the Q¹-Z—group optionally bears 1, 2 or 3 substituents, which may be the same ordifferent, selected from halogeno, trifluoromethyl, cyano, nitro,hydroxy, amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl,(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy,(1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,(2-6C)alkanoyloxy, (2-6C)alkanoylamino,N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl,N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino andN-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of theformula: —X⁸—R¹⁵  wherein X⁸ is a direct bond or is selected from O andN(R¹⁶), wherein R¹⁶ is hydrogen or (1-6C)alkyl, and R¹⁵ ishalogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl,cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl ordi-[(1-6C)alkyl]amino-(1-6C)alkyl, or from a group of the formula:—X⁹-Q⁹  wherein X⁹ is a direct bond or is selected from O, CO andN(R¹⁷), wherein R¹⁷ is hydrogen or (1-6C)alkyl, and Q⁹ is aryl,aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl which optionally bears 1 or 2 substituents,which may be the same or different, selected from halogeno, (1-6C)alkyland (1-6C)alkoxy, and wherein any heterocyclyl group within the Q¹-Z—group optionally bears 1 or 2 oxo or thioxo substituents.
 3. Aquinazoline derivative of the Formula I according to claim 1, or apharmaceutically-acceptable salt thereof, wherein each of m, R¹, R², R³and Q² has any of the meanings defined in claim 1 and Z is selected fromO, S, SO, SO₂, N(R¹¹), CO, CH(OR¹¹), CON(R¹¹), N(R¹¹)CO, SO₂N(R¹¹),N(R¹¹)SO₂, OC(R¹¹)₂, SC(R¹¹)₂ and N(R¹¹)C(R¹¹)₂, wherein R¹¹ is hydrogenor (1-6C)alkyl; and Q¹ is (3-7C)cycloalkyl,(3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl orheterocyclyl-(1-6C)alkyl, and wherein adjacent carbon atoms in any(2-6C)alkylene chain within the Q¹-Z— group are optionally separated bythe insertion into the chain of a group selected from O, S, SO, SO₂,N(R¹²), CO, CH(OR¹²), CON(R¹²), N(R¹²)CO, SO₂N(R¹²), N(R¹²)SO₂, CH═CHand C≡C wherein R¹² is hydrogen or (1-6C)alkyl, and wherein any CH₂ orCH₃ group within the Q¹-Z— group optionally bears on each said CH₂ orCH₃ group one or more halogeno or (1-6C)alkyl substituents or asubstituent selected from hydroxy, cyano, amino, carboxy, carbamoyl,(1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl,(1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,(1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,or from a group of the formula: —X⁷-Q⁸  wherein X⁷ is a direct bond oris selected from O, S, SO, SO₂, N(R¹⁴), CO, CH(OR¹⁴), CON(R¹⁴),N(R¹⁴)CO, SO₂N(R¹⁴), N(R¹⁴)SO₂, C(R¹⁴)₂O, C(R¹⁴)₂S and N(R¹⁴)C(R¹⁴)₂,wherein R¹⁴ is hydrogen or (1-6C)alkyl, and Q⁸ is aryl,aryl-(1-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl,(3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl,heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, andwherein any heterocyclyl group within the Q¹-Z— group optionally bears1, 2 or 3 substituents, which may be the same or different, selectedfrom halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy,carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy,(2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio,(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino,di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,(1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,or from a group of the formula: —X⁸—R¹⁵  wherein X⁸ is a direct bond oris selected from O and N(R¹⁶), wherein R¹⁶ is hydrogen or (1-6C)alkyl,and R¹⁵ is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl,(1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,(1-6C)alkylamino-(1-6C)alkyl or di-[(1-6C)alkyl]amino-(1-6C)alkyl, orfrom a group of the formula: —X⁹-Q⁹  wherein X⁹ is a direct bond or isselected from O, CO and N(R¹⁷), wherein R¹⁷ is hydrogen or (1-6C)alkyl,and Q⁹ is aryl, aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl,heterocyclyl or heterocyclyl-(1-6C)alkyl which optionally bears 1 or 2substituents, which may be the same or different, selected fromhalogeno, (1-6C)alkyl and (1-6C)alkoxy, and wherein any heterocyclylgroup within the Q¹-Z— group optionally bears 1 or 2 oxo or thioxosubstituents.
 4. A quinazoline derivative of the Formula I according toclaim 1, or a pharmaceutically-acceptable salt thereof, wherein each ofm, R¹, R², R³, Z and Q¹ has any of the meanings defined in claim 1 andQ² is an aryl group of formula Ia

 wherein G¹ is halogeno or trifluoromethyl, each of G² and G⁵ ishydrogen, G³ is selected from hydrogen, halogeno, trifluoromethyl,cyano, hydroxy, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and(1-6C)alkoxy, and G⁴ is halogeno or (1-6C)alkoxy.
 5. A quinazolinederivative of the Formula I according to claim 1, or apharmaceutically-acceptable salt thereof, wherein each of m, R¹, R², R³,Z and Q¹ has any of the meanings defined in claim 1 and Q² is an arylgroup of formula Ia wherein G¹ and G² together form a group of formula:—O—CH₂—O—, each of G³ and G⁴, which may be the same or different, isselected from hydrogen, halogeno, trifluoromethyl, cyano, hydroxy,(1-6C)alkyl and (1-6C)alkoxy, and G⁵ is halogeno.
 6. A quinazolinederivative of the Formula I according to claim 1 wherein: m is 0 or m is1 and the R¹ group is located at the 6- or 7-position and is selectedfrom hydroxy, amino, methyl, ethyl, propyl, methoxy, ethoxy, propoxy,methylamino, ethylamino, dimethylamino, diethylamino, acetamido,propionamido, benzyloxy, 2-imidazol-1-ylethoxy,2-(1,2,4-triazol-1-yl)ethoxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1)-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy,piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy,2-piperidin-4-ylethoxy, 2-homopiperidin-1-ylethoxy,3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-homopiperazin-1-ylethoxy and3-homopiperazin-1-ylpropoxy, and wherein adjacent carbon atoms in any(2-6C)alkylene chain within a R¹ substituent are optionally separated bythe insertion into the chain of a group selected from O, NH, CH═CH andC≡C, and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group a substituent selected from hydroxy,amino, methoxy, methylsulphonyl, methylamino and dimethylamino, andwherein any phenyl or heterocyclyl group within a substituent on R¹optionally bears 1 or 2 substituents, which may be the same ordifferent, selected from fluoro, chloro, trifluoromethyl, hydroxy,amino, methyl, ethyl and methoxy, and wherein any heterocyclyl groupwithin a substituent on R¹ optionally bears 1 or 2 oxo substituents; theQ¹-Z— group is selected from propoxy, isopropoxy, 2-hydroxyethoxy,3-hydroxypropoxy, 2-methoxyethoxy, 3-methoxypropoxy, cyclopentyloxy,cyclohexyloxy, phenoxy, benzyloxy, tetrahydrofuran-3-yloxy,tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, 2-imidazol-1-ylethoxy,2-(1,2,4-triazol-1-yl)ethoxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy,piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy,2-piperidin-4-ylethoxy, 2-homopiperidin-1-ylethoxy,3-homopiperidin-1-ylpropoxy, homopiperidin-3-yloxy,homopiperidin-4-yloxy, homopiperidin-3-ylmethoxy,2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy,2-homopiperazin-1-ylethoxy or 3-homopiperazin-1-ylpropoxy, and whereinany CH₂ or CH₃ group within the Q¹-Z— group optionally bears on eachsaid CH₂ or CH₃ group a substituent selected from hydroxy, amino,methoxy, methylsulphonyl, methylamino and dimethylamino, and wherein anyphenyl or heterocyclyl group within the Q¹-Z— group optionally bears 1or 2 substituents, which may be the same or different, selected fromfluoro, chloro, trifluoromethyl, hydroxy, amino, methyl, ethyl andmethoxy, and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo substituents; each of R² and R³ is hydrogen;and Q² is an aryl group of formula Ia

 wherein G¹ is selected from fluoro, chloro, bromo, iodo,trifluoromethyl, cyano, methyl, ethyl, vinyl, allyl, isopropenyl,ethynyl, methoxy and ethoxy, and each of G², G³, G⁴ and G⁵, which may bethe same or different, is selected from hydrogen, fluoro, chloro, bromo,trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl,isopropenyl, ethynyl, methoxy and ethoxy,  or G¹ and G² together form agroup of formula: —CH═CH—CH═CH—, —O—CH═CH— or —O—CH₂—O—, and the 9- or10-membered bicyclic heteroaryl or heterocyclic ring so formedoptionally bears on the heteroaryl or heterocyclic portion of thebicyclic ring 1 or 2 substituents, which may be the same or different,selected from fluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy,methyl, ethyl, methoxy and ethoxy, and any bicyclic heterocyclic ring soformed optionally bears 1 or 2 oxo or thioxo groups, and each of G³, G⁴and G⁵, which may be the same or different, is selected from hydrogen,fluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl,methoxy and ethoxy; or a pharmaceutically-acceptable acid-addition saltthereof.
 7. A quinazoline derivative of the Formula I according to claim1 wherein: m is 0 or m is 1 and the R¹ group is located at the 6- or7-position and is selected from hydroxy, amino, methyl, ethyl, propyl,methoxy, ethoxy, propoxy, methylamino, ethylamino, dimethylamino,diethylamino, acetamido, propionamido, benzyloxy, 2-imidazol-1-ylethoxy,2-(1,2,4-triazol-1-yl)ethoxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy,piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy,2-piperidin-4-ylethoxy, 2-homopiperidin-1-ylethoxy,3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-homopiperazin-1-ylethoxy and3-homopiperazin-1-ylpropoxy, and wherein adjacent carbon atoms in any(2-6C)alkylene chain within a R¹ substituent are optionally separated bythe insertion into the chain of a group selected from O, NH, CH═CH andC≡C. and wherein any CH₂ or CH₃ group within a R¹ substituent optionallybears on each said CH₂ or CH₃ group a substituent selected from hydroxy,amino, methoxy, methylsulphonyl, methylamino and dimethylamino, andwherein any phenyl or heterocyclyl group within a substituent on R¹optionally bears 1 or 2 substituents, which may be the same ordifferent, selected from fluoro, chloro, trifluoromethyl, hydroxy,amino, methyl, ethyl and methoxy, and wherein any heterocyclyl groupwithin a substituent on R¹ optionally bears 1 or 2 oxo substituents; theQ¹-Z— group is selected from phenoxy, benzyloxy,tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,tetrahydropyran-4-yloxy, 2-imidazol-1-ylethoxy,2-(1,2,4triazol-1-yl)ethoxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy,piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy,2-piperidin-4-ylethoxy, 2-homopiperidin-1-ylethoxy,3-homopiperidin-1-ylpropoxy, homopiperidin-3-yloxy,homopiperidin-4-yloxy, homopiperidin-3-ylmethoxy,2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy,2-homopiperazin-1-ylethoxy or 3-homopiperazin-1-ylpropoxy, and whereinany CH₂ or CH₃ group within the Q¹-Z— group optionally bears on eachsaid CH₂ or CH₃ group a substituent selected from hydroxy, amino,methoxy, methylsulphonyl, methylamino and dimethylamino, and wherein anyphenyl or heterocyclyl group within the Q¹-Z— group optionally bears 1or 2 substituents, which may be the same or different, selected fromfluoro, chloro, trifluoromethyl, hydroxy, amino, methyl, ethyl andmethoxy, and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo substituents; each of R² and R³ is hydrogen;and Q² is an aryl group of formula Ia

 wherein G¹ is selected from fluoro, chloro, bromo, iodo,trifluoromethyl, cyano, methyl, ethyl, vinyl, allyl, isopropenyl,ethynyl, methoxy and ethoxy, and each of G², G³, G⁴ and G⁵, which may bethe same or different, is selected from hydrogen, fluoro, chloro, bromo,trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl,isopropenyl, ethynyl, methoxy and ethoxy,  or G¹ and G² together form agroup of formula: —CH═CH—CH═CH—, —O—CH═CH— or —O—CH₂—O—, and the 9- or10-membered bicyclic heteroaryl or heterocyclic ring so formedoptionally bears on the heteroaryl or heterocyclic portion of thebicyclic ring 1 or 2 substituents, which may be the same or different,selected from fluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy,methyl, ethyl, methoxy and ethoxy, and any bicyclic heterocyclic ring soformed optionally bears 1 or 2 oxo or thioxo groups, and each of G³, G⁴and G⁵ which may be the same or different, is selected from hydrogen,fluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl,methoxy and ethoxy; or a pharmaceutically-acceptable acid-addition saltthereof.
 8. A quinazoline derivative of the Formula I according to claim1 wherein: m is 1 and the R¹ group is located at the 7-position and isselected from hydroxy, methoxy, ethoxy, propoxy, benzyloxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy,2-[(2S)-2-N-methylcarbamoyl)pyrrolidin-1-yl]ethoxy,2-[(2S)-2-(N,N-dimethylcarbamoyl)pyrrolidin-1-yl]ethoxy,2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 3-methoxypropoxy,2-methylsulphonylethoxy, 3-methylsulphonylpropoxy,2-(2-methoxyethoxy)ethoxy, 2-(4-pyridyloxy)ethoxy, 2-pyridylmethoxy,3-pyridylmethoxy and 4-pyridylmethoxy; and wherein any CH₂ group withina R¹ substituent that is attached to two carbon atoms optionally bears ahydroxy group on said CH₂ group; the Q¹-Z— group is selected fromtetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy,N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 3-piperidinyloxy, N-methylpiperidin-3-yloxy,4-piperidinyloxy, N-methylpiperidin-4-yloxy, piperidin-3-ylmethoxy,N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy,N-methylpiperidin-4-ylmethoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, cyclobutyloxy, cyclopentyloxy andcyclohexyloxy, and wherein any CH₂ group within the Q¹-Z— group that isattached to two carbon atoms optionally bears a hydroxy group on saidCH₂ group; and wherein any heterocyclyl group within the Q¹-Z— groupoptionally bears 1 or 2 oxo substituents; each of R² and R³ is hydrogen;and Q² is an aryl group of formula Ia

 wherein G¹ is selected from fluoro, chloro, bromo, iodo,trifluoromethyl, cyano, methyl, ethyl, vinyl, isopropenyl, ethynyl,methoxy and pyrrolidin-1yl, G² is hydrogen, each of G³ and G⁴, which maybe the same or different, is selected from hydrogen, fluoro, chloro,bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl,isopropenyl, ethynyl, methoxy and ethoxy, and G⁵ is hydrogen or methoxy, or G¹ and G² together form a group of formula: —CH═CH—CH═CH—, —O—CH═CH—or —O—CH₂—O—, and the 9- or 10-membered bicyclic heteroaryl orheterocyclic ring so formed optionally bears on the heteroaryl orheterocyclic portion of the bicyclic ring 1 or 2 substituents, which maybe the same or different, selected from fluoro, chloro, bromo,trifluoromethyl, cyano, hydroxy, methyl and methoxy, and each of G³, G⁴and G⁵, which may be the same or different, is selected from hydrogen,fluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl andmethoxy; or a pharmaceutically-acceptable acid-addition salt thereof. 9.A quinazoline derivative of the Formula I according to claim 1 wherein:m is 1 and the R¹ group is located at the 7-position and is selectedfrom methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, 2-fluoroethoxy,2,2,2-trifluoroethoxy, benzyloxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy,2-morpholinoethoxy, 3-morpholinopropoxy,2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy,2-homopiperidin-1-ylethoxy, 3-homopiperidin-1-ylpropoxy,2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy,2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy,3-(4-cyanomethylpiperazin-1-yl)propoxy,2-[(2S)-2-carbamoylpyrrolidin-1-yl]ethoxy,2-[(2S)-2-(N-methylcarbamoyl)pyrrolidin-1-yl]ethoxy,2-[(2S)-2-(N,N-dimethylcarbamoyl)pyrrolidin-1-yl]ethoxy,3-methylsulphonylpropoxy, piperidin-4-ylmethoxy,N-methylpiperidin-4-ylmethoxy, 2-(4-pyridyloxy)ethoxy, 2-pyridylmethoxy,3-pyridylmethoxy, 4-pyridylmethoxy and 2-cyanopyrid-4-ylmethoxy, andwherein any CH₂ group within a R¹ substituent that is attached to twocarbon atoms optionally bears a hydroxy group on said CH₂ group; theQ¹-Z— group is selected from tetrahydropyran-4-yloxy,3-pyrrolidin-1-ylpropoxy, N-methylpyrrolidin-3-yloxy,3-morpholinopropoxy, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy,2-piperidinoethoxy, 4-piperidinyloxy, N-methylpiperidin-4-yloxy,piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy,3-(4-methylpiperazin-1-yl)propoxy, cyclopentyloxy and cyclohexyloxy;each of R² and R³ is hydrogen; and Q² is an aryl group of formula Ia

 wherein G¹ is selected from chloro, bromo, trifluoromethyl, methyl,methoxy and pyrrolidin-1-yl, G² is hydrogen, G³ is selected fromhydrogen and chloro, G⁴ is methoxy, and G⁵ is hydrogen,  or G¹ and G²together form a group of formula: —O—CH═CH—, —O—CH═C(Cl)— or —O—CH₂—O—,each of G³ and G⁴ is hydrogen, and G⁵ is hydrogen or chloro; or apharmaceutically-acceptable acid-addition salt thereof.
 10. Aquinazoline derivative of the Formula I according to claim 1 wherein: mis 1 and the R¹ group is located at the 7-position and is selected frommethoxy, ethoxy, propoxy, isopropoxy, isobutoxy, 2-fluoroethoxy,2,2,2-trifluoroethoxy, benzyloxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,3-(4-hydroxypiperidin-1-yl)propoxy, 2-piperidin-4-ylethoxy,2-(N-methylpiperidin-4-yl)ethoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy,2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy,3-(4-cyanomethylpiperazin-1-yl)propoxy,2-[(2S)-2-carbamoylpyrrolidin-1-yl]ethoxy,2-[(2S)-2-(N-methylcarbamoyl)pyrrolidin-1-yl]ethoxy,2-[(2S)-2-(N,N-dimethylcarbamoyl)pyrrolidin-1-yl]ethoxy,3-methylsulphonylpropoxy, piperidin-4-ylmethoxy,N-methylpiperidin-4-ylmethoxy 2-(4-pyridyloxy)ethoxy, 2-pyridylmethoxy,3-pyridylmethoxy and 4-pyridylmethoxy; the Q¹-Z— group is selected fromtetrahydropyran-4-yloxy, 4-piperidinyloxy, N-methylpiperidin-4-yloxy,piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, cyclopentyloxy andcyclohexyloxy; each of R² and R³ is hydrogen; and Q² is an aryl group offormula Ia

 wherein G¹ and G² together form a group of formula: —O—CH₂—O—, each ofG³ and G⁴ is hydrogen, and G⁵ is chloro; or apharmaceutically-acceptable acid-addition salt thereof.
 11. Aquinazoline derivative of the Formula I according to claim 1 selectedfrom:4-(2-chloro-5-methoxyanilino)-5,7-di-(3-morpholinopropoxy)quinazoline,4-(2-bromo-5-methoxyanilino)-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline,4-(2-chloro-5-methoxyanilino)-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline,4-(2-chloro-5-methoxyanilino)-7-[3-(4-methylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazoline,4-(2-chloro-5-methoxyanilino)-7-(3-morpholinopropoxy)-5-tetrahydropyran-4-yloxyquinazoline,4-(2-chloro-5-methoxyanilino)-7-[2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazoline,4-(2-chloro-5-methoxyanilino)-7-(2-hydroxy-3-morpholinopropoxy)-5-tetrahydropyran-4-yloxyquinazoline,4-(2-chloro-5-methoxyanilino)-7-[3-(4-methylpiperazin-1-yl)propoxy]-5-tetrahydrofuran-3-yloxyquinazoline,4-(2-chloro-5-methoxyanilino)-7-(3-morpholinopropoxy)-5-tetrahydrofuran-3-yloxyquinazoline,4-(5-chloronaphth-1-ylamino)-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline,4-(3-chlorobenzofuran-7-ylamino)-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline,7-benzyloxy-4-(2-bromo-5-methoxyanilino)-5-piperidin-4-yloxyquinazoline,4-(2-bromo-5-methoxyanilino)-7-(3-methylsulphonylpropoxy)-5-piperidin-4-yloxyquinazoline,4-(2-bromo-5-methoxyanilino)-7-methoxy-5-piperidin-4-ylmethoxyquinazoline,4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline,4-(2,5-dimethoxyaniline)-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline,4-(2,4-dichloro-5-methoxyanilino)-7-(2-pyrrolidin-1-ylethoxy)-5-tetrahydropyran-4-yloxyquinazoline,4-(2,4-dichloro-5-methoxyanilino)-7-(2-piperidinoethoxy)-5-tetrahydropyran-4-yloxyquinazoline,4-(2,4-dichloro-5-methoxyanilino)-7-(2-morpholinoethoxy)-5-tetrahydropyran-4-yloxyquinazoline,4-(2,4-dichloro-5-methoxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline,4-(2-bromo-5-methoxyanilino)-7-(2-pyrrolidin-1-ylethoxy)-5-tetrahydropyran-4-yloxyquinazoline,4-(2-bromo-5-methoxyanilino)-7-(2-piperidinoethoxy)-5-tetrahydropyran-4-yloxyquinazoline,4-(2-bromo-5-methoxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline,4-(2-bromo-5-methoxyanilino)-7-(4-pyridyloxyethoxy)-5-tetrahydropyran-4-yloxyquinazoline,4-(2-bromo-5-methoxyanilino)-7-{2-[(2S)-2-(N,N-dimethylcarbamoyl)pyrrolidin-1-yl]ethoxy}-5-tetrahydropyran-4-yloxyquinazoline,4-(2-bromo-5-methoxyanilino)-7-{2-[(2S)-2-(N-methylcarbamoyl)pyrrolidin-1-yl]ethoxy}-5-tetrahydropyran-4-yloxyquinazoline,4-(2-bromo-5-methoxyanilino)-7-(4-pyridylmethoxy)-5-tetrahydropyran-4-yloxyquinazoline,4-(5-methoxy-2-pyrrolidin-1-ylanilino)-7-[3-(4-methylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazolineand4-(2-bromo-5-methoxyanilino)-5-cyclopentyloxy-7-(2-pyrrolidin-1-ylethoxy)quinazoline;or a pharmaceutically-acceptable acid-addition salt thereof.
 12. Aquinazoline derivative of the Formula I according to claim 1 selectedfrom:4-(6-chloro-2,3-methylenedioxyanilino)-5-cyclopentyloxy-7-(2-pyrrolidin-1-ylethoxy)quinazoline,4-(6-chloro-2,3-methylenedioxyanilino)-5-piperidin-4-yloxyquinazoline,4-(6-chloro-2,3-methylenedioxyanilino)-7-methoxy-5-piperidin-4-yloxyquinazoline,4-(6-chloro-2,3-methylenedioxyanilino)-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline,4-(6-chloro-2,3-methylenedioxyanilino)-7-methoxy-5-piperidin-4-ylmethoxyquinazoline,4-(6-chloro-2,3-methylenedioxyanilino)-7-(2-pyrrolidin-1-ylethoxy)-5-tetrahydropyran-4-yloxyquinazoline,4-(6-chloro-2,3-methylenedioxyanilino)-7-(3-pyrrolidin-1-ylpropoxy)-5-tetrahydropyran-4-yloxyquinazoline,4-(6-chloro-2,3-methylenedioxyanilino)-7-[3-(4-methylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazoline,4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline,4-(6-chloro-2,3-methylenedioxyanilino)-7-(2-piperidinoethoxy)-5-tetrahydropyran-4-yloxyquinazoline,4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-pyridyloxy)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline,4-(6-chloro-2,3-methylenedioxyanilino)-7-piperidin-4-ylmethoxy-5-tetrahydropyran-4-yloxyquinazolineand4-(6-chloro-2,3-methylenedioxyanilino)-7-(N-methylpiperidin-4-ylmethoxy)-5-tetrahydropyran-4-yloxyquinazoline;or a pharmaceutically-acceptable acid-addition salt thereof.
 13. Aprocess for the preparation of a quinazoline derivative of the FormulaI, or a pharmaceutically-acceptable salt thereof, according to claim 1which comprises: (a) the reaction of a quinazoline of the Formula II

 wherein L is a displaceable group and Q¹, Z, m, R¹ and R² have any ofthe meanings defined in claim 1 except that any functional group isprotected if necessary, with an aniline of the Formula Q²NHR³  whereinQ² and R³ have any of the meanings defined in claim 1 except that anyfunctional group is protected if necessary, whereafter any protectinggroup that is present is removed by conventional means; (b) for theproduction of those compounds of the Formula I wherein Z is an oxygenatom, the coupling of an alcohol of the Formula Q¹-OH  wherein Q¹ hasany of the meanings defined in claim 1 except that any functional groupis protected if necessary with a quinazoline of the Formula IV

wherein m, R¹, R², R³ and Q² have any of the meanings defined in claim 1except that any functional group is protected if necessary, whereafterany protecting group that is present is removed by conventional means;(c) for the production of those compounds of the Formula I wherein m is1 and R¹ is a group of the formula Q³-X¹— wherein Q³ is anaryl-(1-6C)alkyl, (3-7C)cycloalkyl-(1-6C)alkyl,(3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl-(1-6C)alkyl orheterocyclyl-(1-6C)alkyl group and X¹ is an oxygen atom, the coupling ofa quinazoline of the Formula VI

 wherein Q¹, Z, R², R³ and Q² have any of the meanings defined in claim1 except that any functional group is protected if necessary, with anappropriate alcohol wherein any functional group is protected ifnecessary, whereafter any protecting group that is present is removed byconventional means; (d) for the production of those compounds of theFormula I wherein R¹ is a hydroxy group, the cleavage of a quinazolinederivative of the Formula I wherein R¹ is a (1-6C)alkoxy or arylmethoxygroup; (e) for the production of those compounds of the Formula Iwherein Q¹, R¹ or Q² contains a primary or secondary amino group, thecleavage of the corresponding compound of Formula I wherein Q¹, R¹ or Q²contains a protected primary or secondary amino group; (f) for theproduction of those compounds of the Formula I wherein Q¹, R¹ or Q²contains a (1-6C)alkoxy or substituted (1-6C)alkoxy group or a(1-6C)allylamino or substituted (1-6C)alkylamino group, the alkylationof a quinazoline derivative of the formula I wherein Q¹, R¹ or Q²contains a hydroxy group or a primary or secondary amino group asappropriate; (g) for the production of those compounds of the Formula Iwherein Q¹, R¹ or Q² contains an amino-hydroxy-disubstituted(1-6C)alkoxy group, the reaction of a compound of the Formula I whereinQ¹, R¹ or Q² contains an epoxy-substituted (1-6C)alkoxy group with aheterocyclyl compound or an appropriate amine; (h) the reaction of aquinazoline of the Formula VII

 wherein L is a displaceable group and m, R¹, R², R³ and Q² have any ofthe meanings defined in claim 1 except that any functional group isprotected if necessary, with a compound of the Formula Q¹ZH  wherein Q¹and Z have any of the meanings defined in claim 1 except that anyfunctional group is protected if necessary, whereafter any protectinggroup that is present is removed by conventional means; or (i) for theproduction of those compounds of the Formula I wherein Q¹, R¹ or Q²contains an amino-substituted (1-6C)alkoxy group, the reaction of acompound of the Formula I wherein Q¹, R¹ or Q² contains ahalogeno-substituted (1-6C)alkoxy group with a heterocyclyl compound oran appropriate amine; and when a pharmaceutically-acceptable salt of aquinazoline derivative of the Formula I is required it may be obtainedusing a conventional procedure.
 14. A pharmaceutical composition whichcomprises a quinazoline derivative of the Formula I, or apharmaceutically-acceptable thereof, as defined in claim 1 inassociation with a pharmaceutically-acceptable diluent or carrier.
 15. Aquinazoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined in claim 1 for usein a method of treatment of the human or animal body by therapy.
 16. Theuse of a quinazoline derivative of the Formula I, or apharmaceutically-acceptable salt thereof, as defined in claim 1 in themanufacture of a medicament for use as an anti-invasive agent in thecontainment and/or treatment of solid tumour disease.